New Findings in the Control of Stem Cell Differentiation

Nodal Activin Pathways Image Source
Researchers from the Genome Institute of Singapore have helped to untangle how stem cells might be controlled with a single signaling pathway -- the nodal activin pathway.

Morphogens are secreted signaling molecules that orchestrate the spatial distribution and sequence of cellular differentiation events throughout embryonic development. The specific cell types, their localization and order of induction from recipient stem cell populations are determined by the concentration gradient of morphogens diffusing from the source of secretion. Previous studies have proposed some of the models by which morphogen gradients are initiated, established and stabilized including the level of receptor occupancy, positive/negative feedback and feed forward mechanisms [1]–[3]. However, little is understood about the transcriptional mechanisms responding to variable receptor activation and how they permit pluripotent stem cells to interpret signaling levels and direct the appropriate differentiation programs during mammalian development....

Nodal and Activin are morphogens of the TGFbeta superfamily of signaling molecules that direct differential cell fate decisions in a dose- and distance-dependent manner. During early embryonic development the Nodal/Activin pathway is responsible for the specification of mesoderm, endoderm, node, and mesendoderm. In contradiction to this drive towards cellular differentiation, the pathway also plays important roles in the maintenance of self-renewal and pluripotency in embryonic and epiblast stem cells. The molecular basis behind stem cell interpretation of Nodal/Activin signaling gradients and the undertaking of disparate cell fate decisions remains poorly understood. Here, we show that any perturbation of endogenous signaling levels in mouse embryonic stem cells leads to their exit from self-renewal towards divergent differentiation programs. Increasing Nodal signals above basal levels by direct stimulation with Activin promotes differentiation towards the mesendodermal lineages while repression of signaling with the specific Nodal/Activin receptor inhibitor SB431542 induces trophectodermal differentiation. To address how quantitative Nodal/Activin signals are translated qualitatively into distinct cell fates decisions, we performed chromatin immunoprecipitation of phospho-Smad2, the primary downstream transcriptional factor of the Nodal/Activin pathway, followed by massively parallel sequencing, and show that phospho-Smad2 binds to and regulates distinct subsets of target genes in a dose-dependent manner. Crucially, Nodal/Activin signaling directly controls the Oct4 master regulator of pluripotency by graded phospho-Smad2 binding in the promoter region. Hence stem cells interpret and carry out differential Nodal/Activin signaling instructions via a corresponding gradient of Smad2 phosphorylation that selectively titrates self-renewal against alternative differentiation programs by direct regulation of distinct target gene subsets and Oct4 expression. _PLoS Genetics

This finding has profound implications for experimental approaches to guided stem cell differentiation and / or stem cell self renewal. The ability to control multiple distinct sets of genes by titrating the dose of signaling molecules is likely to prove a very powerful tool for geneticists, stem cell researchers, and bio-developmental scientists.

In other longevity news, a team of scientists from multiple universities has helped elucidate how cryoprotectant molecules protect proteins from freezing. Future research should enlarge the scope of study to discover optimal cryoprotectants for cells, tissues, organs -- and eventually for entire organisms.

It is quite possible that different types and levels of cryoprotectant will prove optimal for different organs and tissues, so that in order to viably freeze and thaw an entire organism -- say, a human being -- a complex process of multiple simultaneous organ infusion with several cryoprotectants would be necessary.

Restoring Lost Memories: Hope for Long-Lived Brains?

Our brains were not really meant to last for 80, 90, 100 years. Metabolic debris accumulates, DNA repair mechanisms break down, and function tends to degenerate at variable rates -- depending upon the individual's lifestyle and genetic complement. Now scientists at USC in Los Angeles are learning how to restore lost memories -- at least in rats.

Theodore Berger at the University of Southern California in Los Angeles, and colleagues, used electrodes implanted within the hippocampus to record patterns of brain activity while rats learned how to operate a sequence of levers to gain a reward.

Next, the team obliterated the memory of the task by injecting chemicals into the hippocampus that block the signalling between neurons needed to access long-term memories. When tested, the rats could no longer perform the task.

However, when the team used the electrodes to stimulate the brain with the same pattern of activity recorded when the rats first learned the task, their ability to operate the levers in the correct sequence was restored. The rats could temporarily access the original memory, even though the chemical blockade was still in place. When fed scrambled versions of the code, the rats could no longer perform the task.

Ultimately, the researchers hope to create implants that contain codes for 20 to 30 simple tasks, enabling people with brain damage to recover basic abilities that have been lost, such as speaking or dressing themselves.

Berger says that encoding these tasks will be very difficult. "These are very basic capabilities that we are investigating, and it has taken us a lot of effort to get this far," he says. _NewScientist

It is unlikely that the USC team actually encoded rat brain activity with any accuracy. Rather, the team was able to encode a sufficient "hint" so as to allow the rats to internally re-assemble or approximate their former memories. Even in a rat's brain, mental codes are more difficult than even the best scientists understand.

But it is a promising beginning that provides hope for the long-lived brains of the future.

Article Abstract from Jnl of Neural Engineering

More on Sleep, ATP, and Adenosine

Sleep Phases and Progression

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.
We spend roughly 1/3 of our lives in the state of sleep. Researchers are beginning to learn why we must do this, and are gleaning hints of possible technologies for bypassing at least part of the sleep imperative, and doing well on less sleep.

“For a long time, researchers have known that sleep deprivation results in increased levels of adenosine in the brain, and has this effect from fruit flies to mice to humans.” Abel said. “There is accumulating evidence that this adenosine is really the source of a number of the deficits and impact of sleep deprivation, including memory loss and attention deficits. One thing that underscores that evidence is that caffeine is a drug that blocks the effects of adenosine, so we sometimes refer to this as ‘the Starbucks experiment.’”

Abel’s research actually involved two parallel experiments on sleep-deprived mice, designed to test adenosine’s involvement in memory impairment in different ways.

One experiment involved genetically engineered mice. These mice were missing a gene involved in the production of glial transmitters, chemicals signals that originate from glia, the brain cells that support the function of neurons. Without these gliatransmitters, the engineered mice could not produce the adenosine the researchers believed might cause the cognitive effects associated sleep deprivation.

The other experiment involved a pharmacological approach. The researchers grafted a pump into the brains of mice that hadn’t been genetically engineered; the pump delivered a drug that blocked a particular adenosine receptor in the hippocampus. If the receptor was indeed involved in memory impairment, sleep-deprived mice would behave as if the additional adenosine in their brains was not there.

...To see whether these mice showed the effects of sleep deprivation, the researchers used an object recognition test. On the first day, mice were placed in a box with two objects and were allowed to explore them while being videotaped. That night, the researchers woke some of the mice halfway through their normal 12-hour sleep schedule.

On the second day, the mice were placed back in the box, where one of the two objects had been moved, and were once again videotaped as they explored to see how they reacted to the change.

“Mice would normally explore that moved object more than other objects, but, with sleep deprivation, they don’t,” Abel said. “They literally don’t know where things are around them.”

Both sets of treated mice explored the moved object as if they had received a full night’s sleep.

“These mice don’t realize they’re sleep-deprived,” Abel said.

Abel and his colleagues also examined the hippocampi of the mice, using electrical current to measure their synaptic plasticity, or how strong and resilient their memory-forming synapses were. The pharmacologically and genetically protected mice showed greater synaptic plasticity after being sleep deprived than the untreated group.

Combined, the two experiments cover both halves of the chemical pathway involved in sleep deprivation. The genetic engineering experiment shows where the adenosine comes from: glia’s release of adenosine triphosphate, or ATP, the chemical by which cells transfer energy to one another. And the pharmacological experiment shows where the adenosine goes: the A1 receptor in the hippocampus. _MedicalXpress

Abel's is a sophisticated experiment which covers a lot of possiblities. Combining the findings of this experiment with findings of previous experiments gives one a fuller picture of what is going on.
The brain has evolved certain activity in N2 sleep (sleep spindles) which apparently promotes the production of ATP from adenosine and phosphate groups. As ATP levels rise in N2 sleep, adenosine levels drop. So the sound sleeper receives both the benefits of higher ATP energy levels and the improved learning that results from lower hippocampal free adenosine levels.

More on sleep spindles (PDF)

Adenosine is a potent pharmacological agent, powerfully affecting heart rhythms. It also affects central nervous system activity in a largely inhibitory function, and also exhibits anti-inflammatory effects.

Adenosine and deep brain stimulation (DBS)

Why Do We Sleep? A brief look at stages of sleep, and possible benefits of sleep.

Cross posted to Al Fin, the Next Level

How could we manage on less sleep? The fastest route to achieving high-functioning sleep reduction would seem to involve electromagnetic brain stimulation or inhibition over particular brain areas at specific pulse frequencies. The aim would be to reduce adenosine levels -- and increase ATP levels -- in specific areas of the brain including the hippocampus.

Pharmacological methods for blocking adenosine's effect, such as used in the experimental mice in the study above, offer another possiblity -- although a time delay before approval for a new drug of at least 10 years is to be expected.

Genetic techniques for modifying adenosine production or re-uptake and ATP synthesis, are another likely approach -- eventually. At the present time, genetic (and epigenetic) treatment methods are far too primitive and clumsy to risk for such an objective as sleep reduction, for most people.

Other neuromolecules are likely involved in this puzzle, but at least this information offers a place to start.

Refurbishing the Brain, Making Humans Smarter and Happier

“I think we’re getting closer to harnessing neurogenesis to improve cognition and mood in humans. This research may also help explain a bit of a mystery in the field, which we still don’t understand, regarding how the hippocampus can be involved with both cognition – which is its classic function – and in mood and anxiety-related functions. Perhaps the fact that pattern separation affects both the cognitive and mood domains is the beginning of an answer to that paradox,” said Dr. Hen. _StemCells

René Hen, PhD, professor of Neuroscience and Pharmacology, in the Departments of Neuroscience and Psychiatry at Columbia University and the New York State Psychiatric Institute, has discovered a possible escape hatch by which some members of society might escape the Idiocracy. It involves the use of chemicals called "BAX inhibitors." Particular members of that class of drugs have the potential to preserve newborn stem cells in the brain's hippocampus. And doing that could make all the difference in the course of a person's life success and happiness.

After boosting the number of neurons in the hippocampus, an area of the brain involved in memory and mood, the researchers tested the mice in both learning and mood-related tasks and looked for changes in behavior. The researchers found specific effects on learning tasks that involve a process called pattern separation, which is the ability to distinguish between similar places, events and experiences.

“This process is crucial for learning because it enables us to know whether something is familiar or novel,” said Dr. Hen. “If it is familiar, you move on to the next bit of information; if it’s novel, you want to be able to recognize that it’s new and give it meaning. These mice, with just more adult-born neurons, and no other changes in the brain, basically learn better in tasks where they have to discriminate between similar contexts.”

Earlier strategies for manipulating neurogenesis, according to the investigators, were broader and less specific. “In addition to stimulating neurogenesis, these earlier methods exerted many other effects on the brain. As a result, you never knew with these older manipulations what’s due to neurogenesis, or what’s due to the other effects that these manipulations cause, and, indeed, what we find is that when you stimulate just adult neurogenesis, you actually get a subtle effect. Unlike broader manipulations, it does not affect all forms of learning, it’s very specific to tasks that require pattern separation,” said Dr. Hen.

Pattern separation is not only important for learning; it may also be important for anxiety disorders, including post traumatic stress disorder (PTSD) and panic disorder. People with PTSD, say the researchers, have a more generalized fear response, so that when they are placed in a situation that reminds them of even one aspect of their trauma, they frequently have a full fear response.

...The researchers say that the genetic strategy used to stimulate neurogenesis in their experiments can be mimicked pharmacologically, potentially leading to the development of new drugs to reverse pattern separation deficits. One such class of drugs the investigators are currently testing – BAX inhibitors – works by blocking cell death.

“These drugs are basically doing the same thing that we did with our genetic manipulation-namely, increasing the survival of the young neurons which normally undergo a process of cell death that eliminates at least half of these neurons. Now instead of dying, the neurons will go on to survive,” said Dr. Sahay.

Some BAX inhibitors have been developed for stroke research, where the goal has also been to prevent neurons from dying. The Columbia researchers plan to begin testing the BAX inhibitors in mice shortly. And if they produce cognitive benefits, the testing will be extended to clinical trials to determine if there’s also a beneficial effect in humans. _StemCells

This is all related to the length of time required before antidepressants are able to bring about a full "antidepressive response." The full effect of modern antidepressants requires new stem cell production in the hippocampus -- but that takes time to achieve. Drugs capable of rapid and prolonged increases of hippocampal stem cells could conceivably keep anxiety and depression at bay, while improving a person's cognitive capacity.

No, this is not NZT. As mentioned here previously, a drug that could achieve the effect of the fictional NZT would have to stimulate changes in gene expression on multiple levels, and across a wide range of brain centers.

Smart drugs alone will not achieve the goal of smarter, better-rounded, and happier humans. Educational and environmental interventions would also be necessary, to blunt the Idiocratic brainwashing effect of modern media, modern academia, and modern popular culture, while allowing the brain to develop newer, more functional pathways.

Realistically, it will take 15 years at the earliest to see the early promise of this type of medication come to fulfillment. But a single ray of hope in the distance is worth a lot to a person immersed in the modern rush to Idiocracy.

More 5April2001: An example of rapid brain plasticity in human adults
The PNAS Abstract from the actual study

Previously published at Al Fin

As noted here before, improved neurogenesis in the hippocampus is associated with antidepressant and anti-anxiety behaviours in animal studies -- and probably in humans. It does no good to live longer with younger brains if we are unable to enjoy our added time and brainpower.

Inflammation Kills! Blocking the Inflammation After MI, CVA

Blocking Complement
A person may survive a severe heart attack (MI) or stroke (CVA) only to succumb to the effects of devastating inflammation which tends to occur after blood supply is restored to tissue that was damaged from temporary loss of perfusion. An effective treatment for preventing such re-perfusion inflammation could save many hundreds of thousands of lives a year.

The lectin pathway is responsible for the potentially devastating inflammatory tissue response that can occur when any bodily tissue or organ is reconnected to blood supply following ischaemia – a temporary loss of that blood supply and the oxygen that it carries. This excessive inflammatory response is, in part, responsible for the morbidity and mortality associated with myocardial infarction (heart attack) and cerebrovascular accidents (CVAs or strokes). Moreover, the work succeeded in finding a way to neutralise this enzyme by raising a therapeutic antibody against it. A single antibody injection in animals has been shown to be sufficient to disrupt the molecular process that leads to tissue and organ destruction following ischaemic events, resulting in significantly less damage and markedly improved outcomes.

"This is a fascinating new achievement in the search for novel treatments to significantly reduce the tissue damage and impaired organ function that occur following ischaemia in widespread and serious conditions such as heart attacks and strokes," said Professor Schwaeble. "This new potential therapy was also shown in animals to significantly improve outcomes of transplant surgery and may be applicable to any surgical procedure where tissue viability is at risk due to temporary interruption of blood flow. _Eurekalert

Of course Professor Schwaeble is correct. Not only would such a treatment be a potential blockbuster drug for preventing complications from MI and CVA, but it would also be immensely useful for surgical procedures where blood supply is temporarily interrupted, or for treating cases of trauma where blood supply is interrupted by the trauma itself and/or by a lifesaving procedure such as a tourniquet or MAST suit used to prevent fatal exsanguination.

The University of Leicester led an international team whose research has been published today in the Early Online Edition of the Proceedings of the National Academy of Sciences (PNAS).

Professor Wilhelm Schwaeble of the Department of Infection, Immunity and Inflammation at the University of Leicester, initiated and co-ordinated research collaborations with King's College London, the Medical University of Fukushima, Japan and the State University of New York, to achieve the present breakthrough findings, which were published today in PNAS.

Professor Schwaeble and collaborators identified an enzyme, Mannan Binding Lectin-Associated Serine Protease-2 (MASP-2), that is found in blood and is a key component of the lectin pathway of complement activation, a component of the innate immune system. _Eurekalert

Total Brain Network Imaging Reveals Efficiency Loss w/ Ageing

“While particular brain regions are important for specific functions, the capacity of information flow within and between regions is also crucial,” said study leader Scientia Professor Perminder Sachdev from UNSW’s School of Psychiatry.

“We all know what happens when road or phone networks get clogged or interrupted. It’s much the same in the brain.

“With age, the brain network deteriorates and this leads to slowing of the speed of information processing, which has the potential to impact on other cognitive functions.” _Science Alert

University of New South Wales researchers have utilised advanced diffusion tensor imaging (PDF research article) along with powerful computational tools to assess the efficiency of the total brain network of white matter, and watched overall brain processing speeds as they slow due to ageing.

The research team, led by Scientia Professor Perminder Sachdev from the UNSW School of Psychiatry, has mapped the network of fibres or ‘white matter’ for the first time, allowing them to examine the strength of connections between different cortical regions, or ‘grey matter’, which are responsible for specific functions. In the past, most research has focused on the more complicated grey matter without looking at how information flows between separate regions.

A new type of magnetic resonance imaging (MRI) called diffusion tensor imaging (DTI) combined with powerful computers allowed the team to create the map and see the whole network in great detail.

“Using a mathematical theory you can see how strongly the different regions are connected to each other,” Professor Sachdev said. “You can basically look at the efficiency of the network and with ageing, we can see a reduction in the efficiency of these networks.”

“What we wanted to see is how this relates to cognitive function, and we found that the best relationship was with processing speed, which makes sense because we’re talking about strength of information connections.”

Other areas strongly affected by the efficiency of neural networks were executive functions that manage other brain processes and the ability to navigate in space, known as visuospatial function.

Sachdev said the findings could help to some extent with dementia research, by offering another way of looking at the condition, but had already helped explain what happens in the brain when physical reaction time slows down in older people.

“It’s not that they can’t do the task, it just takes longer, and we have shown that this is related to structural changes in the brain, in terms of its neural networks.”

“The next step is looking at what determines the efficiency of these networks. We want to see if they are flexible or plastic, and whether maybe we can intervene.”

...The results of the study, which was based on a sample of 342 healthy people aged between 72 and 92, have been published in the January edition of the Journal of Neuroscience. _AustralianAgeingAgenda

Here is more from science alert Australia:

In the study, the researchers performed magnetic resonance imaging (MRI) scans on 342 healthy individuals aged 72 to 92, using a new imaging technique called diffusion tensor imaging (DTI).

Using a mathematical technique called graph theory, they plotted and measured the properties of the neural connectivity they observed.

“We found that the efficiency of the whole brain network of cortical fibre connections had an influence on processing speed, visuospatial function – the ability to navigate in space – and executive function,” said study first author Dr Wei Wen.

“In particular greater processing speed was significantly correlated with better connectivity of nearly all the cortical regions of the brain.”

Professor Sachdev said the findings help explain how cognitive functions are organised in the brain, and the more highly distributed nature of some functions over others. _Science Alert

It is important to stress the difference between speed of nerve transmission and speed of information processing for the brain. The two are related, and both are measurable (or calculable) using the DTI computational techniques, but information processing is a much higher order process than mere nerve conduction velocities. Knowing processing speeds -- particularly being able to compare whole brain processing and subsystem processing speeds and efficiencies -- provides more information.

Diffusion Tensor Imaging (DTI) can be used to assess several aspects of brain functioning, including general intelligence and executive function. It can also be used to assess multiple types of brain pathology, including schizophrenia.

Better brain imaging techniques provide clinicians and researchers with better information with which to form theories and plan therapies. As brain ageing comes to be seen more as a reversible pathology, more advanced diagnostic tools and therapeutic methods will be made available more widely.

Are We Closer to Viable Long-Term Freezing for Organs and People?

Once we are able to viably freeze and thaw living organs and whole animals, without damage or injury, we will be able to plan for the targeted freezing and thawing of living humans for purposes of extended survival.

A technology that has come from the frozen sushi industry in Japan is being studied for possible application to living animals and human organs such as hearts, livers, lungs, and kidneys.

A technology used to freeze sushi is solving a dilemma for organ storage. By borrowing tech used to preserve high-end food delicacies, a Hiroshima University research group proved it possible to safely freeze whole teeth and their delicate attaching tissues. As long as the freezer stays cold, the folks at Hiroshima U. think your teeth could be stored for 40 years, no problem.

But the sushi-storage system isn’t a one trick pony: internal organs could be next thanks to the magic of supercooling. In typical cryo-storage, fast freezing of organs requires poisonous levels of anti-freeze, and let’s face it, no one wants a poisoned kidney transplanted into their body. But slower freezing causes cell popping ice crystals to form.

So, what do you do to prevent ice crystals during slow freezing? Use magnets. ABI is the Japanese company producing the freezer system. ABI’s “Cells Alive System” (CAS) vibrates water with magnetic fields, preventing freezing, even at supercool temperatures of -10 degrees Celsius (According to the Patent.) When the field is turned off, the water in the food instantly freezes. No time for ice growth means no Freddy Krueger action on frozen organs.

...The transition of this tech from food to longevity science is slowly evolving, but the steps forward are real. You can, right now, pay to store your teeth. Hiroshima University tested the cooling technology for teeth, and uses ABI CAS freezer tech at The Teeth Bank, the world’s first commercial tooth bank. Dr. Toshitsugu Kawata, a Hiroshima University professor who has done extensive research at the Teeth Bank, helped prove that CAS is a viable technology to preserve teeth. Spare teeth used to be worthless medical waste. Now, removed wisdom teeth aren’t garbage, they can be frozen and re-implanted at any point during your life.

...The founder of the ABI Corporation and its CAS freezer, Norio Owada (known internationally as “Mr. Freeze,”) is actively pursuing medical advances. There’s a hodgepodge of reports out there about what’s being done. According to various sources, Mr. Freeze is collaborating with 40 researchers to translate their work with teeth and sushi to hearts, nerves, and other organs. Transplant medicine could benefit tremendously. With further research, this technology could supercool, or even freeze internal organs, putting an end to the dangerously brief time frame for organ transplants. In a 2008 Forbes article, Mr. Freeze speculated on where his technology may lead. “If you could preserve a heart for three days, you could fly it anywhere.” On the late-night Japanese TV show, World Business Satellite, there was discussion of research towards using ABI’s CAS freezers to store ovaries during cancer treatment, allowing women to keep their fertility. On the ABI company webpage, photos of a rat heart transplant and undamaged cell walls of frozen wasabi are a reminder of the unusual coupling of frozen food and medicine. _SingularityHub_via_NextBigFuture

One further step is needed: a vitrification agent which can be added to the supercooled organs which would allow the electromagnetic field to be turned off without the risk of freezing. One step at a time.

The Virtues of Experience

Wikipedia
The human brain learns a lot, over time. Experience shapes the brain, determining how it will work, and which parts of the brain will be active in different circumstances. Recent Japanese brain research has determined that expert players in the Japanese chess game "Shogi" use a different part of their brain (the caudate nucleus) to play, than do amateurs of the game. The caudate nucleus is the curved purple structure in the image above.

Neuroscientists at the RIKEN Brain Science Institute in Wako, Japan, studied a group of professional and amateur shogi players. Shogi is the Japanese version of chess. With the use of real-time brain scans, the researchers discovered that the pros activated different parts of their brains than the amateurs did while studying game patterns and contemplating their next moves.

The findings were published in the Jan. 21 issue of Science.

Senior study author Keiji Tanaka, deputy director of the institute and head of the Cognitive Brain Mapping Laboratory, said the experts' unique brain circuitry enabled them to have "superior intuitive problem-solving capabilities."

Professional shogi players, who have practiced three or four hours a day for several years, "repeatedly note that the best next move comes to their mind 'intuitively,'" the authors wrote. "Being 'intuitive' indicates that the idea for a move is generated quickly and automatically without conscious search, and the process is mostly implicit."

...r brain difference occurred when the players were forced to quickly pick their next best move. The professionals' brain scans revealed activity in a portion of the basal ganglion known as the caudate nucleus, while the amateurs' scans did not.

The researchers suggest that a unique circuit between these two regions of the brain is what enables professional players to expertly recognize board game patterns and quickly choose their optimal next move.

"There was no volume difference of the caudate nucleus between professional and amateur players," said Tanaka. This suggests that "the caudate nucleus is used for other purposes in ordinary people [but] the experts have developed a unique way to use the system." _BW_via_ImpactLab

The caudate nucleus has been implicated in the development of automaticity of several types -- which places the caudate in a central, pivotal position for humans living in modern societies.

First, the caudate appears to be involved in the acquired automaticity of motor skills. This is not such a big surprise to brain researchers. But the caudate also seems to be involved in the automaticity of emotional processing, the automaticity of perceptual categorisation (PDF), automaticity of rule-based categorisation, and in switching between two languages in bilingual individuals. There are almost certainly more caudate functions to come.

Sure, there is overlap between the different caudate functions, but the brain -- and its many modular parts -- is nothing if not multi-functional. A Swiss Army knife of cognitive and emotional tools that modifies itself over a person's lifetime, adapting to the individual's experience.

That is why it is so important to the individual that the brains many potential functions be developed before their developmental windows close. And why it is so important to society that the brains of its members are well developed and long-lived.

We cannot afford to waste all of that hard-earned knowledge, experience, and savvy by dying too young. 500 year lifespans should be seen as a minimum timespan for skills acquisition and for passing these skills along to future generations.

DNA for Healthy Aging, and Rebuilding the Brain After Stroke

We will look at two studies that relate to the quest for longer, healthier, more productive and fulfilling lives. First, researchers at the University of Miami looked at an Amish population and discovered that a certain genetic pattern in the mitochondria seems to allow for a much healthier lifespan into the 80s.

On Friday they will present a paper showing that 15 percent of healthy Amish octogenarians have "haplogroup X," a genetic pattern within the mitochondria, which are the regions of cells that generate energy and help guard against deterioration. Haplogroup X is generally found in only 2 percent of Europeans, from whom the Amish descended. In the University of Miami study, only 3 percent of the control group—Amish people who had made it to 80 but suffered from significant disease or disability—had the genetic variant. The paper will be featured during a session at the American Society of Human Genetics' annual meeting in Washington, D.C.

Researchers who study aging have long suspected that mitochondria play a role in aging. Mitochondria are responsible for processing metabolized food particles into adenosine triphosphate, which fuels vital cellular processes. They're also involved in cell growth and differentiation. But the ability of mitochondria to function properly seems to decline with age.

Understanding the reason for that decline—and the genes that might control it—has been challenging. Mitochondria have their own DNA, which is passed down from the mother only. This unique chromosome has variations, called haplogroups. Nine such haplogroups have been well characterized in people of European descent, Scott says. But only haplogroup X was found to be prevalent among healthy aged people in the University of Miami study. _TechnologyReview

The second study, from UCLA researchers, looks at the ability of the brain to re-build following stroke -- or brain infarct. The team appears to have discovered a drug target with significant promise, which may lead to drugs that help the brain to re-build itself following destructive lesions.

A stroke is usually caused by a clot that blocks blood flow to an area of the brain. Tissue in that part of the brain dies from lack of oxygen unless the clot is detected immediately and is either dissolved or removed. The dead tissue cannot be revived, but often the brain can be trained to redirect nerve impulses via still-living nearby neurons. But such training is difficult, can require months to years of arduous rehab, and is often not sufficient to overcome complex disability.

The new research, by neurologist S. Thomas Carmichael and his colleagues at the University of California at Los Angeles, shows that neurons in the areas of the brain closest to the site of a stroke are impaired after it occurs. The reason for that is a buildup of an inhibitory signaling molecule called GABA that prevents the neurons from firing. When those nerves are inhibited, it's harder for the brain to recruit them into its rerouted circuits.

In studies in mice, the researchers discovered that blocking a particular piece of the GABA signaling system with an existing drug allowed the nerves to reactivate, reversing the repressed excitability, allowing them to more easily respond to other neurons, and encouraging and enhancing early recovery after a stroke by as much as 50 percent. "At face value, it's a new pharmacological target for repair and recovery in stroke," Carmichael says.

...Carmichael and his colleagues identified the piece of the GABA signaling cascade that goes awry in the area of the brain adjacent to the stroke: reduced levels of a transporter responsible for moving the inhibitory molecule out of the vicinity. Without that transporter, GABA is allowed to reach such high levels that the nearby neurons are prevented from firing.

In studies in mice, the researchers induced a stroke in the motor cortex, the movement center of the brain, and then gave them a drug that specifically reverses the post-stroke GABA uptake. The drug is not approved for use in people—it was an experimental molecule produced during the drug industry's search for memory enhancers. But just the fact that it works in mice means that stroke researchers have a new line of evidence to pursue.

"It's significant, because they're identifying a molecular mechanism that is keeping stroke survivors from recovering. And as a result, [Carmichael is] identifying targets for molecular manipulation," says Theresa Jones, a neurobiologist at the University of Texas at Austin. "Now we have potential to find drugs that aim at that target."

The scientists found that, as with other types of stroke treatments, timing was critical. During the first few days after a stroke, a brain injury is still stabilizing; prior studies have shown that any physical rehabilitation attempted during this period can aggravate the brain and actually make the damage worse. The same proved true for the drug.

But when the mice were given the drug three days later, it improved their recovery of movement by 40 to 50 percent. This implies that while the post-stroke inhibition of neurons in these areas may help with immediate recovery, but it is a harmful adaptation when it persists for weeks or months or even years after the initial injury. _TechnologyReview

Stroke is one of the major causes of death and disability in the developed world. A viable treatment for stroke rehabilitation would be a significant medical development.

Reversing Age Related Memory Loss

Researchers estimate that roughly 20 to 30 percent of people age 75 and older have elevated glucocorticoid levels (more precise figures aren't available). Most affected is so-called declarative memory, the ability to learn new facts and remember, for example, lists. People who suffer age-related memory loss are at higher risk for developing Alzheimer's and other forms of dementia, though the condition is not itself considered a form of dementia. _TechnologyReview

A research team at the University of Edinburgh have developed a new compound that appears to prevent and reverse age-related memory decline in mice. Their approach utilises a "gene knockout" approach against an amplifier of glucocorticoid effect present in brain cells.

"What's most surprising is that even short-term inhibition was able to reverse memory loss in old mice," says Jonathan Seckl, a professor of molecular medicine who was involved in the research. "I don't think people had realized this was so reversible. It takes [the animals] back to being relatively young."

The researchers hope to develop equivalent human therapies and are now more extensively studying the safety of a closely related compound in animals. They aim to begin human testing within a year.

Scientists have long known that glucocorticoids--a class of steroid hormones that mediate our response to stressful situations--play a role in age-related memory decline. Although short-term exposure to glucocorticoids enhances the formation of memories during stressful situations, chronically high levels of the hormones are linked to greater memory loss with age, both in humans and animals. The exact mechanism underlying this link is unclear, but researchers theorize that excess exposure to the hormones makes parts of the brain more vulnerable to damage.

Seckl and his collaborators focused on an enzyme called 11β-hydroxysteroid dehydrogenase type 1 (11 β-HSD1). This enzyme generates an active version of the key glucocorticoid hormone within brain cells and some other tissues, providing a target for fine-tuning the system without blocking the overall stress response. Tinkering with the enzyme seems to have little effect on blood levels of glucocorticoids, which are produced in the adrenal glands. Instead, "this enzyme acts as an intracellular amplifier of glucocorticoids," says Seckl. "If you take out the amplifier, you still have stress hormones, but they shout less loudly and cause less wear and tear."

The Edinburgh team showed that knocking out either one or both copies of the gene for this enzyme in mice preserved the animals' memory into old age. To determine whether blocking the enzyme could improve memory in already aged animals, researchers then developed a compound designed to cross into the brain and inhibit the enzyme. Just 10 days of treatment in two-year-old mice--the maximum lifespan for a typical lab mouse--was enough to improve the animals' performance on a test of spatial memory. The treatment "returned mice to the equivalent of when they were young and fully functioning," says Brian Walker, another researcher involved in the study. "It's important to emphasize that we are trying to target the pathology--the role that glucocorticoids play in age-related memory decline--not just globally improving memory." The research was published last week in the Journal of Neuroscience. _TechnologyReview

Brian Wang looks at another approach to augmenting human brainpower

Also published at Al Fin

Open Source Biotechnology: The Wonder and the Terror

As recently as a decade ago, the tools and techniques for such fiddling were confined to a handful of laboratories like those at leading research universities. Today, do-it-yourself biology clubs have sprung up where part-timers share tips on how to build high-speed centrifuges, isolate genetic material, and the like. The movement has been aided by gear that can turn a backyard shed into a microbiology lab. _WSJ

With the emergence of open-source biohacking, a number of scientists and authorities are starting to worry about the possibility that a biohacker will create some type of super-microbe which could cause a significant disease outbreak. Here you can find a zipped download introduction to biohacking.

The new fear, though, is that scientific advances that enable amateur scientists to carry out once-exotic experiments, such as DNA cloning, could be put to criminal use. Many well-known figures are sounding the alarm over the revolution in biological science, which amounts to a proliferation of know-how—if not the actual pathogens.

"Certain areas of biotechnology are getting more accessible to people with malign intent," said Jonathan Tucker, an expert on biological and chemical weapons at the James Martin Center for Nonproliferation Studies.

Geneticist Craig Venter said last month at the first meeting of a presidential commission on bioethics, "If students can order any [genetic sequences] online, somebody could try to make the Ebola virus."

Mr. Venter is a pioneer in the field whose creation of a synthetic organism this spring helped push the debate about the risks and rewards of bioscience from scientific journals to the corridors of power in Washington. "We are limited more by our imagination now than any technological limitations," Mr. Venter said.

Scientists have the ability to manipulate genetic material more quickly and more cheaply all the time. Just as "Moore's Law" describes the accelerating pace of advances in computer science, advances in biology are becoming more potent and accessible every year, experts note. _WSJ

Of all the things likely to escape from garage biohacking outposts, none are likely to bring about the end of the human species. Some of them may even be beneficial for health and long life.

Just as some of the fastest developments in personal computing emerged from basements and garages, so is it possible for home-based biohackers to make important contributions to bioscience and biomedicine. Curiosity drives most small scale hacking of all kinds -- the desire to understand how things work.

For humans who are interested in going beyond the ordinary in terms of lifespan, intelligence, sleep requirements, strength, speed, etc. the answers may well arise from small scale independent labs -- given how over-regulated and over-restricted all aspects of government sanctioned biomedicine are becoming in western countries.

Is there a danger? Yes, there is always a danger, and all of us should stay alert for persons who seem to be several cards short of a full deck. But that shouldn't stop us from pushing the limits.

Regenerative Medicine Advances

The promise of regenerative medicine involves a future where replacement organs and tissues can be re-grown in a lab from a person's own cells, then transplanted into the person as brand-new, fully functioning replacement tissue. Replacement lung tissue, replacement heart tissue, replacement ligaments and tendons, replacement skin, kidneys, muscle, intestine, bladders, and on and on. But first, scientists have to find a good way to grow millions and billions of healthy stem cells from a person's own cells, and keep them alive long enough to turn them into the proper tissue, and grow them on a proper scaffold into the proper replacement organs.

Investigators from the Massachusetts Institute of Technology (MIT) recently developed a new type of support structure for stem cells, which allows them to remain alive for weeks without using any foreign genetic material.

Generally, substrates for growing stem cells contain animal cells or tissue, but these can easily contaminate the samples themselves, which means that they can lose some of their capabilities.

This is an especially serious consequence for induced pluripotent stem cells, which are biological units that can transform into any type of tissue in the human body.

Only environmental conditions dictate whether they will turn into nerve cells, or into pancreatic tissue.

Due to this amazing differentiation ability they have, these cells hold great promise for treating a number of disorders, such as for example Parkinson's, multiple sclerosis and spinal cord injuries.

But, in order to make the best of them, researchers need to be able to grow them in sufficiently large quantities, and this is proving to be extremely difficult due to the lack of proper substrates.

One of the main issues in this field of research is the fact that human stem cells are now grown with the aid of cells or proteins derived from mice embryos. If these foreign chemicals would interact with the human body, they would definitely cause an allergic reaction.

Thanks to the MIT collaborations, which includes biologists, materials engineers and chemists, scientists now have a synthetic surface that features no material from mice or other animals.

The data the team recorded of the new surfaces show that they promote and sustain “all-natural” stem cell growth and reproduction for at least three months. Longer periods are also possible, the group says.

Another impressive feat the MIT experts achieved with their new material is the fact that it allows for researchers to separate colonies of identical cells from each other. The surface allows single cells to form colonies of cells of that type with considerable ease.

Details of the new investigation appear in the August 22 issue of the esteemed scientific publication Nature Materials, e! Science News reports. _Softpedia

Another report from ScienceDaily

“For therapeutics, you need millions and millions of cells. If we can make it easier for the cells to divide and grow, that will really help to get the number of cells you need to do all of the disease studies that people are excited about,' says MIT postdoctoral associate Krishanu Saha, one of the co-first authors of the paper. 

The work was led by MIT professors Robert Langer, Rudolf Jaenisch and Daniel G. Anderson, in collaboration with Saha and postdoctoral researcher Ying Mei. _Softpedia

This report from Brian Wang on Swiss stem cell research, suggests that mature tissue-derived stem cells can be programmed across germ layer boundaries. This finding hints at the possibility of creating virtually any type of cell or tissue from any other type of tissue -- including easily sampled tissues such as skin or blood.

Cross-posted at Al Fin

The Aging Brain: Endangered by Runaway Development?

Mehmet Somel, a Turkish researcher doing post-doctoral work in Shanghai, has uncovered some fascinating genetic evidence suggesting that inappropriate-for-age gene regulation may be endangering aging brains:

Researchers have now identified a gene regulatory link between changes in the young and aging brain.

The brain undergoes rapid growth and development in the early years of life and then degenerates as we progress into old age, yet little is known about the biological processes that distinguish brain development and aging.

Underlying brain development is the complex and coordinated process of gene regulation.

"In development, many genes are turned on and off by regulators, such as transcription factors and microRNAs. The question is, do all of these regulatory processes cease once adulthood is reached, or are they still active in aging?" said Mehmet Somel, postdoctoral researcher at the Shanghai Institutes for Biological Sciences.

The researchers investigated messenger RNA (mRNA), microRNA, and protein expression changes in the prefrontal cortex of humans and rhesus macaque monkeys over the life span of each species.

The group found that distinct patterns of gene regulation in the prefrontal cortex do not stop at maturity, instead persisting into old age, a phenomenon that was observed for many different functional processes.

...The researchers showed that this process begins as early as three to four years of age, suggesting that these changes may be normal developmental regulation that continues long into old age.

While this regulation is likely to be beneficial during development, at old age continuation of the gene regulation, or "runaway" development, might be detrimental.

Interestingly, they found the runaway neuronal development to be conserved in macaques, but it occurs an accelerated rate.

Because the regulatory processes progress much faster, the authors suggest that this could be a significant contributor toward limiting the life span of macaques to only about one-third that of humans. _SiFy

Researchers will now need to determine whether a more "age-appropriate" pattern of gene regulation would allow for persistence of normal brain functioning further into old age.

It is known that DNA repair loses efficiency with increasing age. If inappropriate genes are consistently "over-clocked" at levels more appropriate to younger ages, the compounding of genetic errors due to inefficient DNA repair would occur more quickly and take on more significance.

This is a fascinating area of study, well worth following.

Can Delaying Puberty & Extending Childhood Increase Lifespan?

Puberty seems to be arriving at earlier ages for both boys and girls. There are many reasons why puberty onset is earlier now, but most of these reasons are still unclear. The problems that arise from premature puberty include violence, higher risks of cancer and diabetes, increased behavioural problems (drugs, alcohol, delinquency etc), isolation from peer groups -- even a change in growth rates for the children of girls with premature onset of puberty.

ImageSource

...children who go into early puberty are prematurely sexualised and too immature to deal with the implications. They are more vulnerable to sexual abuse, inappropriate sexual behaviour, sexually transmitted diseases and teenage pregnancy. “It means that children develop sexually much earlier,” Stanhope says. “They are physically ready for sexual reproduction but mentally completely unready.”

Studies have shown that adolescents who go through puberty earlier are involved in more risk-taking behaviour, such as taking drugs, binge drinking and breaking the law. A premature increase in testosterone can lead to aggression in boys who lack the maturity to control impulses. “We all realise that testosterone is a very difficult hormone to learn to live with,” Stanhope says, tapping a pencil vigorously on his pockmarked table, “and if you get a rise in testosterone outside the normal physiological age, then it’s even more of a problem.”

Research published this year in the Australian and New Zealand Journal of Criminology also found increased aggression in girls who reached puberty early. In Britain the uncomfortable reality that children are becoming sexually mature earlier has been overlooked in the recent debate about the over-sexualisation of children. Instead of simply focusing on cynical manufacturers producing padded bras for seven-year-olds, perhaps we should also consider how to respond to the new reality that some girls are now growing breasts at this age.

Stanhope also points out that for women there may be long-term health problems, because early puberty increases exposure to oestrogen. According to Cancer Research UK, a girl who has her first period a year later than her contemporaries has 5% less risk of developing breast cancer in later life. “There may be an important link with breast and ovarian cancer,” Stanhope says. “The earlier a girl has her period, the longer her exposure to oestrogen and this may well have very important sequelae for oestrogen-dependent tumours. This increases her risk of breast cancer, ovarian cancer and of developing cardiovascular problems.”

Girls who reach puberty early are also more likely to develop type 2 diabetes. A 37-year-long study of 61,000 Norwegian women showed that women who got their first period at ten or 11 had a 10% higher mortality rate than those who got their period four years later. _PubertyBlues

Scientists are beginning to home in on the physiological initiators of puberty, and have found a way to delay puberty in mice. By "knocking out" a specific gene, IGF-1R, researchers have both delayed puberty and maintained normal reproductive function after puberty in these knockout mice.

Pubertal onset, initiated by pulsatile gonadotropin-releasing hormone (GnRH), only occurs in a favorable, anabolic hormonal milieu. Anabolic factors that may signal nutritional status to the hypothalamus include the growth factors insulin and IGF-1. It is unclear which hypothalamic neuronal subpopulation these factors affect to ultimately regulate GnRH neuron function in puberty and reproduction. We examined the direct role of the GnRH neuron in growth factor regulation of reproduction using the Cre/lox system. Mice with the IR or IGF-1R deleted specifically in GnRH neurons were generated. Male and female mice with the IR deleted in GnRH neurons displayed normal pubertal timing and fertility, but male and female mice with the IGF-1R deleted in GnRH neurons experienced delayed pubertal development with normal fertility. With IGF-1 administration, puberty was advanced in control females, but not in females with the IGF-1R deleted in GnRH neurons, in control males, or in knockout males. These mice exhibited developmental differences in GnRH neuronal morphology but normal number and distribution of neurons. These studies define the role of IGF-1R signaling in the coordination of somatic development with reproductive maturation and provide insight into the mechanisms regulating pubertal timing in anabolic states. _JCI

Scientists will find additional triggers for pubertal onset besides insulin and IGF-1, and some of those factors may provide a more benign approach to the delaying of puberty.

Paradoxically, IGF-1 is vital for normal development of mice, but knocking out IGF-1 receptors in certain flies and worms can increase lifespan. That paradox is still being studied.

So -- how long should puberty be delayed, if at all? If childhood could be extended for several more years without impairing the ability of the child to learn and mature psychologically, would the potential health and societal benefits be worth the postponement of sexual development of the child?

What if aging itself were to be postponed along with puberty? If total lifespan were extended by the number of extra years a person spent in childhood, would that be beneficial to society or not? What if a person could live an extra 20, 30, or 50 years -- but had to spend those extra years as a pre-pubertal child. Would it be worth it?

Those who see increased longevity as a sure path to overpopulation collapse of Earth's ecosystem, would insist upon some form of sterilisation for those who opt for longevity. In some countries, laws of that type -- mandating permanent sterilisation for anyone undergoing longevity treatments -- should be expected.

Extended pre-puberty is a form of time-limited and (probably) reversible sterilisation, so any longevity approach that also delayed puberty significantly, should not raise the hackles of those suffering from overpopulation anxiety too much. But there are likely to be a large number of objections to such treatments, all the same.

Modern societies appear to see children in a schizoid manner. Fewer children are born, so the one or two children a family does have, are cherished and pampered. On the other hand, children are seen as a hindrance to a hedonic lifestyle, an exorbitant expense and often a great bother. Overall, most children do not seem to be raised or educated very well in modern societies, judging by observable results.

While childhood is not prolonged in modern societies, an incompetent adolescence is certainly prolonged -- in many cases indefinitely. Given the choice between a prolonged childhood leading into an accelerated but prepared-for adolescence, and the current state of lifelong incompetent adolescence commonly seen in the affluent world, most Al Fin mental health professionals would choose the prolonged childhood combined with a prepared-for adolescence that leads into a responsible and competent adulthood.

Previously published at Al Fin

A New Class of Molecules that May Cure Alzheimer's

New nerve cells are constantly born in the hippocampus, but even in the normal adult brain, most of these newborn neurons die before they become functional.

And they fare much worse in the hippocampus of Alzheimer's patients.

Physical activity, an active social life and other intellectually and emotionally enriching experiences promote the birth and maturation of new neurons.

The scientists wanted to find compounds that can protect newborn neurons from dying.

P7C3 was selected from among about 1,000 compounds tested on mice.

The compound was found to help the survival of neurons in adult mice, which were genetically engineered to lack a gene that is crucial for the survival of newborn nerve cells. _IndiaToday

ScienceDaily
University of Texas Southwestern have reported in Cell the discovery of a molecule -- P7C3 -- that has the ability to protect brain cells, and trigger the production of new neurons. The scientists believe that new compounds in the same class as P7C3 may hold the key to slowing or temporarily reversing the progress of Alzheimer's Disease and other neurodegenerative conditions.

In a new study published today in the journal Cell, researchers screened 1000 molecules in mice to see which ones enhanced production of new neurons in a brain area involved in learning and memory. This region, known as the hippocampus, is one of two spots known to birth new neurons in the adult mammalian brain. It takes 2 to 4 weeks for the cells to migrate to the appropriate location and integrate into the existing neural circuitry, and many of them die along the way.

The researchers found that one compound, dubbed P7C3, protected these newborn neurons from dying. When given to mice genetically engineered to have very little new nerve cell growth, the compound seemed to repair the abnormal hippocampus. It could also increase birth and survival of new neurons in older rats, according to a press release from UT Southwestern Medical Center. The animals also had improved memory: they could better remember the location of a platform submerged in water, a standard test of learning and memory in rodents.

...

According to a release from the journal Cell, where the paper was published;

Two other drugs (Dimebon and Serono compounds) - both of which bear structural similarities to P7C3 -also encourage the growth of new neurons. It's tempting to think that all three compounds work in the same way.

In fact, Dimebon first came to the attention of researchers based on anecdotal reports by Russian physicians that the drug may ameliorate the symptoms of age-related cognitive decline. Unfortunately, unpublished reports from a phase 3 clinical trial have since failed to provide evidence that the drug could stave off the memory loss that comes with Alzheimer's disease.

In light of the new findings, it may be worth another look. "The speculative idea that these chemicals share a common mode of action will only be rigorously tested upon identification of their molecular target(s)."

 _TechnologyReview

Pieper, McKnight and colleagues tested more than 1000 small molecules in living mice. One of the compounds, designated P7C3, corrected deficits in the brains of adult mice engineered to lack a gene required for the survival of newborn neurons in the hippocampus. Giving P7C3 to the mice reduced programmed death of newborn cells -- normalizing stunted growth of branch-like neuronal extensions and thickening an abnormally thin layer of cells by 40 percent. Among clues to the mechanism by which P7C3 works, the researchers discovered that it protects the integrity of machinery for maintaining a cell's energy level.
To find out if P7C3 could similarly stem aging-associated neuronal death and cognitive decline, the researchers gave the compound to aged rats. Rodents treated with P7C3 for two months significantly outperformed their placebo-treated peers on a water maze task, a standard assay of hippocampus-dependent learning. This was traced to a threefold higher-than-normal level of newborn neurons in the dentate gyrus of the treated animals. Rats were used instead of mice for this phase of the study because the genetically engineered mice could not swim.
Prolonged treatment of aged rats with P7C3 also enhanced the birth of new neurons. "Aged rats normally show a decline in neurogenesis associated with an inability to form new memories and learn tasks," Pieper explained.

In their study, rats treated with P7C3 each day showed evidence of an increase in the formation of newborn neurons and significant improvements in their ability to swim to the location of a missing platform, a standardized test of learning and memory in rats.

The researchers pinpointed a derivative of P7C3, called A20, which is even more protective than the parent compound. They also produced evidence suggesting that two other neuroprotective compounds eyed as possible Alzheimer's cures may work through the same mechanism as P7C3. The A20 derivative proved 300 times more potent than one of these compounds currently in clinical trials for Alzheimer's disease. This suggested that even more potent neuroprotective agents could potentially be discovered using the same methods. Following up on these leads, the researchers are now searching for the molecular target of P7C3 -- key to discovering the underlying neuroprotective mechanism. _ScienceDaily

The study was two-tiered: First the scientists screened over a thousand small molecules in knockout mice, to find the one that provided the best protection for new hippocampal neurons. Then they tested the compound in senescent rats, looking for both behavioural improvements and better survival of new hippocampal neurons. They were successful on all counts.

H/T Brian Wang of NextBigFuture

Cross-posted to Al Fin

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.