Progress in Regenerative Medicine: Anthony Atala at Wake Forest University

[Anthony] Atala currently heads up more than 300 researchers in the Wake Forest University lab who are working on growing more than 30 different organs and body tissues.

In one trial for the U.S. Armed Forces, his team is collecting healthy skin cells from injured soldiers, processing them, and then spraying them onto battle wounds as a tailored treatment for healing. For deeper wounds, they are in the process of developing an ink jet printer that scans a wound and creates a custom map of the defect.

"After the scan, the printer can go back and print multiple layers of cells right over the wound," Atala said.

The idea of using a patient's own cells rather than relying on those of a donor is important because it eliminates the need to find a "match." For any transplant procedure there is a concern that tissues from a donor will be rejected by a recipient's body. _ABC_via_NBF

There are many challenges to creating lab-grown replacements for human organs. But the promise of being able to create a perfect tissue match replacement organ, and no longer being forced to wait at the bag of the organ donour line, is simply too great a promise to ignore.

Regenerative Medicine and Organ Transplantation

By the early 1990s, tissue engineering had become an established field of investigation (30). Concurrently, adult stem cells and ESC were isolated in animals (31, 32) and humans (33), and the advent of nuclear transfer technology made animal cloning possible (7, 34–36). These apparently distinct fields of science had one unifying concept, namely the regeneration of living and functioning body parts destined to replace diseased or damaged cells, tissues, or organs (7). In 1999, the term “regenerative medicine” was coined to describe the use of natural human substances, such as genes, proteins, cells, and biomaterials to regenerate diseased or damaged human tissue (4, 7). It is important to note that the terms tissue engineering and regenerative medicine are not synonymous. The term regenerative medicine is used to define a field in the health sciences that aims to replace or regenerate human cells, tissues, or organs to restore or establish normal function (37). The process of regenerating body parts can occur in vivo or ex vivo and may require cells, natural or artificial scaffolding materials, growth factors, or combinations of all three elements. In contrast, the term tissue engineering is narrower in scope and strictly defined as manufacturing body parts ex vivo, by seeding cells on or into a supporting scaffold. _Excerpted from: Regenerative Medicine and Organ Transplantation: Past, Present, and Future (Atala et al)

Since the early days of tissue engineering, advances in stem cell science, genetic engineering, tissue engineering, 3D printing, and related fields, have given the field of regenerative medicine new powers that were not previously imagined. While all of those sciences continue to advance, it remains for the regenerative medicine specialist to bring them all together and create a new state of the art in tissue and organ transplantation.

Transplantation 2011: Regenerative Medicine and Organ Transplantation

One useful "shortcut" in creating new organs from a patient's own tissues, is the use of "acellular" scaffoldings. A donour organ is stripped of its cells, leaving only the supporting acellular matrix scaffolding, including vascular matrix. This scaffolding is then seeded with replacement cells and growth factors for the tissue being replaced, ie vascular, renal, hepatic etc.

Hepatology: Whole Organ Acellular Scaffolds

A significant advancement in the field of bioscaffold design has been the utilization of decellularized tissue as the three-dimensional scaffold in tissue engineering strategies.11 Our laboratory has previously reported the successful decellularization of porcine aortas and urinary bladder submucosa for use as scaffolds for cell seeding.2, 12 These decellularized aortas were seeded with endothelial progenitor cells and implanted into sheep, and the neovessels remained patent for more than 4 months.2 However, effective decellularization of thicker organs and tissues has been very difficult to achieve due to inefficient penetration of the decellularization solution into the organ. More recently, Ott et al. have developed a more effective method for organ decellularization.13 They have shown that by perfusing a detergent solution through the vascular network rather than relying on agitation and diffusion alone, the entire mouse heart could be decellularized and used as a scaffold for tissue engineering. However, cell seeding of three-dimensional, naturally derived scaffolds presents additional challenges.14 For example, to achieve a recellularized human liver adequate for clinical use, one needs to transfer approximately 10 × 1010 liver cells into the scaffold. So far, such a task has not been successfully achieved. Although perfusion bioreactors have been developed to address cell seeding problems,15, 16 cell seeding across the entire thickness of the scaffold has been limited due to the lack of intrascaffold channels.

The goal of our study was to develop a novel scaffold that human liver cells could readily enter in order to repopulate the scaffold volume. We report the production of such a scaffold via a decellularization process that preserves the macrovascular skeleton of the entire liver while removing the cellular components. The intact vascular tree is accessible through one central inlet, which branches into a capillary-like network and then reunites into one central outlet. Human fetal liver and endothelial cells were perfused through the vasculature and were able to repopulate areas throughout the scaffold by engrafting into their putative natural locations in the liver. These cells displayed typical endothelial, hepatic and biliary epithelial markers, thus creating a liver-like tissue in vitro. This technology may provide important tools for the creation of a fully functional bioengineered liver that can be used as an alternative for donor liver transplantation. _Hepatology 2011 (Atala et al)

Ideally, one would wish to grow and/or print the entire organ in the lab, but the intricate 3D complexity of the intercellular scaffolding of many organs makes such a task very difficult at this time.


ABC News Video


Wake Forest video via _PSFK.com

H/T NextBigFuture

AUF1 Hat Trick: Suppresses Inflammation, Reduces Cancer Risk, and Inhibits Cellular Senescence

Researchers at NYU School of Medicine have, for the first time, identified a single gene that simultaneously controls inflammation, accelerated aging and cancer. _NYU SOM

AUF1 is a micro-RNA binding protein that has been found to perform multiple vital cell functions. Engineered mice that lack the AUF1 protein suffer rapid premature aging that worsens with each generation. By replacing AUF1 function in these mice, the harmful premature aging and accelerated cellular senescense can be reversed.

AUF1 binds and strongly activates the transcription promoter for telomerase catalytic subunit Tert. In addition to directing inflammatory cytokine mRNA decay, AUF1 destabilizes cell-cycle checkpoint mRNAs, preventing cellular senescence. Thus, a single gene, AUF1, links maintenance of telomere length and normal aging to attenuation of inflammatory cytokine expression and inhibition of cellular senescence. _Molecular Cell (ScienceDirect)

AUF1 also accelerates the degradation of inflammatory cytokine, reducing the inflammation load on cells and tissues. More from NYU School of Medicine, where much of the recent research on AUF1 was done:

For decades, the scientific community has known that inflammation, accelerated aging and cancer are somehow intertwined, but the connection between them has remained largely a mystery, Dr. Schneider said. What was known, due in part to past studies by Schneider and his team, was that a gene called AUF1 controls inflammation by turning off the inflammatory response to stop the onset of septic shock. But this finding, while significant, did not explain a connection to accelerated aging and cancer.

When the researchers deleted the AUF1 gene, accelerated aging occurred, so they continued to focus their research efforts on the gene. Now, more than a decade in the making, the mystery surrounding the connection between inflammation, advanced aging and cancer is finally being unraveled.

The current study reveals that AUF1, a family of four related genes, not only controls the inflammatory response, but also maintains the integrity of chromosomes by activating the enzyme telomerase to repair the ends of chromosomes, thereby simultaneously reducing inflammation, preventing rapid aging and the development of cancer, Dr. Schneider explained.

“AUF1 is a medical and scientific trinity,” Dr. Schneider said. “Nature has designed a way to simultaneously turn off harmful inflammation and repair our chromosomes, thereby suppressing aging at the cellular level and in the whole animal.”

With this new information, Dr. Schneider and colleagues are examining human populations for specific types of genetic alterations in the AUF1 gene that are associated with the co-development of certain immune diseases, increased rates of aging and higher cancer incidence in individuals to determine exactly how the alterations manifest and present themselves clinically. _NYU

This is an exciting and potentially important finding. But it takes time for exciting research discoveries to be converted into potentially revolutionary therapies against cancer, aging, and crippling inflammatory diseases.

Early attempts to capitalise on this discovery are likely to be disappointing, particularly as expectations will tend to be raised prematurely. But as the ability to generate safe, effective, affordable treatments begins to catch up to the ability to discover the mechanisms of biological function at multiple levels, the pace of change may grow at a startling rate.

The important thing is to get the basic science findings into the hands of the research community for replication, clarification, and elaboration. After that, scientists can begin finding ways to make the research work in favour of an abundant human future.

Original 1997 identification of AUF1 at Rutgers and Wake Forest (PDF)

H/T Nextbigfuture

Intravenous Stem Cells: Where Do They Go? What Do They Do?

We usually think of stem cell therapy in terms of replacing damaged cells or tissues with stem cells, which can differentiate and become the type of cell or tissue which is being replaced. But there is more to it than that, particularly in the case of intravenous stem cell infusion.

Researchers have tracked the migration of stem cells administered intravenously following an injury. At first the majority of the cells lodge within the lung, where they appear to interact with pulmonary macrophages altering the type of cell signaling molecules those macrophages release into the blood. Next the stem cells migrate to the organs of the reticuloendothelial system which includes the spleen. Surprisingly, less than 3% of infused stem cells migrate into brain tissue. So the immunomodulatory effect does not require the majority of infused stem cells to interact directly with injured brain tissue. _SciAm

It turns out that much of the beneficial effect from the intravenous infusion of stem cells comes from their effect on the immune system. IV infused stem cells apparently shift the immune system's response to injury and rejuvenation, creating a more favourable environment for healing and regeneration.

This allows the few stems cells which make it all the way to the damaged tissue, to promote regeneration locally without a harmful immune response.

Immunomodulatory stem cell studies attempt to adjust the immune response in a way that minimizes the damage associated with the initial injury, and then allows the individual’s native repair machinery to function optimally.

With even mild injury, the immune system is activated. Macrophages are a type of immune cell which participate in the post-injury immune response. With “classic” macrophage activation, the immune response is aggressively induced. Classically activated macrophages are described as having an “M1” phenotype. In the nervous system, the M1 immune response can increase the severity of an injury. Alternatively activated or “M2” macrophages, are associated with a less destructive pattern of immune system activation. This alternate/M2 response results in less immune mediated post-injury damage, as well as the possible disinhibition of native nervous system repair.

Following traumatic brain injury (TBI) children experience a loss of 12-15% of their brain tissue in the 12 months following their injury (Levin). In a study where we treated TBI children with their own bone marrow stem cells, there was minimal post injury brain volume loss in the year after TBI (Cox). In animal models of TBI, animals that experienced injury were found to have M1 macrophages throughout their injured brain tissue.

Animals treated with stem cells after TBI were found to have M2 macrophages in their brain parenchyma. Interestingly, if an animal’s spleen was removed before stem cell infusion, the benefit of the stem cell treatment was eliminated. Somehow stem cell infusion causes a change in the pattern of macrophage activation from M1 to M2, which results in a less aggressive immune response and less post-injury brain tissue death. This effect requires an intact spleen. _SciAm

So you see that in an optimal response to stem cell infusion following an injury, the patient will experience both immunomodulatory effect and a regenerative effect from the IV stem cell infusion.

When the stem cells being infused are of a broad-spectrum nature -- such as cord blood, embryonic stem cells, or pluripotent adult stem cells -- the door is wide open for other effects beyond the immunomodulatory and the regenerative (replacement) effects. It should be clear that other rejuvenative effects are also possible from broad spectrum stem cell infusion. It will simply require a good deal of research and consideration before most of those effects can be discovered and decoded for optimal therapies in the future.

Staggered Drug Therapies Hit Some Cancer Cells Harder

This treatment worked not only in cancer cells grown in a lab dish, but also in mice with tumors. When treated with a one-two punch of erlotinib and doxorubicin, the tumors shrank and did not grow back for the duration of the experiment (two weeks). With chemotherapy alone, or when the two drugs were given at the same time, the tumors initially shrank but then grew back. _MIT

Differential cell responses to chemotherapy treatment. The photo shows a range of responses of similar cells to the chemotherapeutic drug doxorubicin. The most intensely responding drugs are shown in yellow, many of which will die. Green cells are alive but not dividing. Red cells are continuing to grow and divide. Yaffe and colleagues have figured out how to increase the proprotion of triple negative breast cancer cells that can be killed by a specific time-ordered regiment of growth factor inhibitors and chemotherapy, with direct application to clinical treatment. Image courtesy of Neil Ganem, Michael Yaffe and David Pellman

Staggering the administration of cancer chemotherapy drugs can effectively treat some types of cancer which are highly resistant to conventional modes of chemotherapy treatment. MIT cancer researchers are leading the research to discover why a staggered treatment seems more effective, and to determine which types of cancer are most susceptible to this method of drug administration.

In the new paper, published in Cell on May 11, the researchers showed that staggering the doses of two specific drugs dramatically boosts their ability to kill a particularly malignant type of breast cancer cells.

The researchers, led by Michael Yaffe, the David H. Koch Professor of Biology and Biological Engineering at MIT, are now working with researchers at Dana-Farber Cancer Institute to plan clinical trials of the staggered drug therapy. Both drugs — erlotinib and doxorubicin — are already approved for cancer treatment.

Yaffe and postdoc Michael Lee, lead author of the Cell paper, focused their study on a type of breast cancer cells known as triple negative, meaning that they don’t have overactive estrogen, progesterone or HER2 receptors. Triple-negative tumors, which account for about 16 percent of breast cancer cases, are much more aggressive than other types and tend to strike younger women.

“For triple-negative breast cancer cells, there is no good treatment. The standard of care is combination chemotherapy, and although it has a good initial response rate, a significant number of patients develop recurrent cancer,” says Yaffe, who is a member of the David H. Koch Institute for Integrative Cancer Research at MIT.

Uncontrolled growth

For the past eight years, Yaffe has been studying the complex cell-signaling pathways that control cells’ behavior: how much they grow, when they divide, when they die. In cancer cells, these pathways often go haywire, causing the cells to grow even in the absence of any stimulus and to ignore signals that they should undergo cell suicide.

Yaffe became intrigued by the idea that drug-induced changes in these signaling pathways, if staggered in time, could switch a cancerous cell into a less malignant state. “Our previous systems-biology work had primed us to the idea that you could potentially drive a cell from a state in which only a fraction of the tumor cells were responsive to chemotherapy into a state where many more of them were responsive by therapeutically rewiring their signaling networks in a very time-dependent way,” he says.

Specifically, he and Lee thought it might be possible to sensitize cancer cells to DNA-damaging drugs — the backbone of most chemotherapy — by first giving them another drug that shuts down one of the haywire pathways that promote uncontrollable growth. They tested different combinations of 10 DNA-damaging drugs and a dozen drugs that inhibit different cancerous pathways, using different timing schedules.

“We thought we would retest a series of drugs that everyone else had already tested, but we would put in wrinkles — like time delays — that, for biological reasons, we thought were important,” Lee says. “I think had it not worked, we would have gotten a lot of pushback, but we were pretty convinced that there was a lot of information being left on the table by everyone else.”

Of all combinations they tried, they saw the best results with pretreatment using erlotinib followed by doxorubicin, a common chemotherapy agent. Erlotinib, approved by the FDA to treat pancreatic cancer and some types of lung cancer, inhibits a protein found on cell surfaces called the epidermal growth factor (EGF) receptor. When constantly active, as it is in many cancer cells, the EGF receptor stimulates a signaling pathway that promotes uncontrolled growth and division.

The researchers found that giving erlotinib between four and 48 hours before doxorubicin dramatically increased cancer-cell death. Staggered doses killed up to 50 percent of triple-negative cells, while simultaneous administration killed about 20 percent. About 2,000 genes were affected by pretreatment with erlotinib, the researchers found, resulting in the shutdown of pathways involved in uncontrolled growth.

“Instead of looking like this classic triple-negative type of tumor, which is very aggressive and fast-growing and metastatic, they lose their tumorigenic quality and become a different type of tumor that is actually quite unaggressive, and very easy to kill,” Lee says.

However, if the drugs were given in the reverse order, doxorubicin became less effective than if given alone.

...A combination of high-throughput measurements and computer modeling was used to reveal the mechanism for increased tumor killing, and to identify a biomarker for drug response. The researchers found that the treatment was most effective in a subset of triple-negative breast cancer cells with the highest levels of EGF receptor activity. This should allow doctors to screen patients’ tumors to determine which would be most likely to respond to this novel treatment.

The research is “groundbreaking in its demonstration that the principles of order and time are essential to the development of effective therapies against complex diseases,” Rune Linding, research group leader at the Technical University of Denmark, and Janine Erler, associate professor at the University of Copenhagen, wrote in a commentary accompanying the paper in Cell. “As disease researchers, we must consider network states, and this and other studies serve as a model for a new generation of cancer biologists.”

The concept of staggering drug treatments to maximize impact could be very broadly applicable, Yaffe says. The researchers found similar boosts in tumor killing by pretreating HER2-positive breast cancer cells with a HER2 inhibitor, followed by a DNA-damaging drug. They also saw good results with erlotinib and doxorubicin in some types of lung cancer.

“The drugs are going to be different for each cancer case, but the concept that time-staggered inhibition will be a strong determinant of efficacy has been universally true. It’s just a matter of finding the right combinations,” Lee says.

The findings also highlight the importance of systems biology in studying cancer, Yaffe says. “Our findings illustrate how systems engineering approaches to cell signaling can have large potential impact on disease treatment,” he says. _MITNews

The scientists have barely begun to discover the mechanisms behind the effectiveness of staggered treatments.

What is not mentioned is that we are likely to discover methods of treating ageing, once we more fully understand the reasons for the success of staggered cancer chemotherapy. Because of the time sensitive nature of DNA repair and epigenetic shifting, certain combinations of interventions which affect the genetic and epigenetic apparatus need to be given at certain times in relation to each other. In other words, some interventions facilitate other interventions, but only for specific periods of time, until the system reverts to its original status.

There is a rich gold mine of discovery associated with this phenomenon. Stem cell research has already confronted this discovery, and is exploring it to good effect. Cancer research is likewise beginning to see the light. Soon, anti-ageing research will wield this powerful tool. Time-sensitive paired (and more) interventions are likely to revolutionise the field of genetic intervention across multiple fields.

Mastering Cell Signaling: A Worthy Goal

Cells make decisions in fluctuating environments using inherently noisy biochemical mechanisms. Such effects create considerable, unpredictable variation – known as ‘stochasticity’– both over time and between genetically identical cells. To understand how cells exploit and control these biochemical fluctuations, scientists must identify the sources of stochasticity, quantify their effects, and distinguish variation that carries information about the biological environment from confounding noise.

In their PNAS paper, Dr Bowsher and Professor Swain show how to decompose the fluctuations of biochemical networks into multiple components and how to design experimental ‘reporters’ to measure these components in living cells.

The paper, which describes the application of this approach to yeast cells, shows that the majority of cellular variation may be informational in origin and due to fluctuations in the cellular environment. The results pave the way to a better understanding of the dynamics of signal processing and decision-making by cells. _SD

Cell Signaling Network, Preliminary Sketch
We begin to comprehend the potential power of cell signaling mastery, when we observe research breakthroughs such as the following:

In laboratory experiments with mouse cells, the researchers found that a specific protein that regulates cell aging also controls a process that causes blood-making stem cells to age. Using drugs to inhibit the action of this protein (called Cdc42) reversed aging of the hematopoietic stem cells and restored their function to a level similar to that of younger stem cells.

It had been [previously] believed that the aging of hematopoietic stem cells was locked in by nature and could not be reversed by using drugs, according to a hospital news release.

...The study by scientists at Cincinnati Children's Hospital Medical Center and Ulm University Medicine in Germany appeared online May 3 in the journal Cell Stem Cell. _USN

Turning old hematopoietic stem cells into young hematopoietic stem cells is nothing to sneeze at. And it is only a slight foretaste of what is becoming possible, as we better understand cell signaling networks and the signaling involved in gene expression.

One of the more exciting near-to-intermediate term possibility arising from the coming mastery of cell signaling, is the ability to reverse neurodegenerative diseases which involve abnormal protein folding. Diseases such as Alzheimer's, Huntington's, Parkinson's, and "mad cow disease," for example, involve abnormal proteins leading to cell destruction and loss of neural function.

Researchers at the University of Leicester uncovered how the build-up of proteins in mice with prion disease resulted in brain cells dying.

They showed that as misfolded protein levels rise in the brain, cells respond by trying to shut down the production of all new proteins.

...The team at the Medical Research Council laboratory in Leicester then tried to manipulate the switch which turned the protein factory off. When they prevented cells from shutting down, they prevented the brain dying. The mice then lived significantly longer.

Each neuro-degenerative disease results in a unique set of misfolded proteins being produced, which are then thought to lead to brain cells dying.

Prof Giovanna Mallucci told the BBC: "The novelty here is we're just targeting the protein shut-down, we're ignoring the prion protein and that's what makes it potentially relevant across the board."

The idea, which has not yet been tested, is that if preventing the shut down protects the brain in prion disease - it might work in all diseases that have misfolded proteins.

Prof Mallucci added: "What it gives you is an appealing concept that one pathway and therefore one treatment could have benefits across a range of disorders. _BBC

Nature article

Complex cell signaling is also involved in the control of gene expression, including critically important DNA repair, and control of telomere length in cells -- which controls the number of cell doublings allowed.

If you click on the image above, you can view an enlarged version of a portion of a cell signaling network. Such complexity explains the need for high powered computational backup in the attempt to decode these networks, as a prelude to their mastery.

Cellular processes take place very quickly, and in a closely controlled and balanced chemical milieu. If we are to learn to intervene on the level of the cell in a beneficial way, we must proceed with care. But we definitely aim to proceed.

Stanford U. Researchers Fire Potent Shot Across the Bow of Solid Tumour Cancers

A single drug can shrink or cure human breast, ovary, colon, bladder, brain, liver, and prostate tumors that have been transplanted into mice, researchers have found. The treatment, an antibody that blocks a "do not eat" signal normally displayed on tumor cells, coaxes the immune system to destroy the cancer cells. _ScienceMagNews

In research published on PNAS (Full PDF), Stanford researchers demonstrated the ability to successfully destroy human cancer growing in mice, using monoclonal antibodies targeted against the cellular protein CD47.

CD47 is overexpressed in many cancers, and allows the tumour cells to "fly beneath the immune system's radar," thus escaping destruction. By blocking CD47, the scientists demonstrated that the immune system was able to destroy tumour cells that would have been otherwise ignored.

To determine whether blocking CD47 was beneficial, the scientists exposed tumor cells to macrophages, a type of immune cell, and anti-CD47 molecules in petri dishes. Without the drug, the macrophages ignored the cancerous cells. But when the CD47 was present, the macrophages engulfed and destroyed cancer cells from all tumor types.

Next, the team transplanted human tumors into the feet of mice, where tumors can be easily monitored. When they treated the rodents with anti-CD47, the tumors shrank and did not spread to the rest of the body. In mice given human bladder cancer tumors, for example, 10 of 10 untreated mice had cancer that spread to their lymph nodes. Only one of 10 mice treated with anti-CD47 had a lymph node with signs of cancer. Moreover, the implanted tumor often got smaller after treatment -- colon cancers transplanted into the mice shrank to less than one-third of their original size, on average. And in five mice with breast cancer tumors, anti-CD47 eliminated all signs of the cancer cells, and the animals remained cancer-free 4 months after the treatment stopped.

"We showed that even after the tumor has taken hold, the antibody can either cure the tumor or slow its growth and prevent metastasis," says Weissman.

Although macrophages also attacked blood cells expressing CD47 when mice were given the antibody, the researchers found that the decrease in blood cells was short-lived; the animals turned up production of new blood cells to replace those they lost from the treatment, the team reports online today in the Proceedings of the National Academy of Sciences.

Cancer researcher Tyler Jacks of the Massachusetts Institute of Technology in Cambridge says that although the new study is promising, more research is needed to see whether the results hold true in humans. "The microenvironment of a real tumor is quite a bit more complicated than the microenvironment of a transplanted tumor," he notes, "and it's possible that a real tumor has additional immune suppressing effects."

Another important question, Jacks says, is how CD47 antibodies would complement existing treatments. "In what ways might they work together and in what ways might they be antagonistic?" Using anti-CD47 in addition to chemotherapy, for example, could be counterproductive if the stress from chemotherapy causes normal cells to produce more CD47 than usual. _SciencemagNews

This approach would probably not qualify as a solo therapy, but would rather be used along with other anti-cancer therapies, to either cure a cancer or to limit its growth and spread where cure is not possible.

Researchers believe that all solid tumours may well be vulnerable to this approach.

This treatment will not be without side effects, and not all cancer patients would benefit or qualify for such treatment. But it is very promising.

H/T NextBigFuture

Another Approach to Treating Alzheimer's In Early Stages

A study published this week in the Journal of Neuroscience shows that the compound epothilone D (EpoD) is effective in preventing further neurological damage and improving cognitive performance in a mouse model of Alzheimer's disease (AD). The results establish how the drug might be used in early-stage AD patients.

...EpoD acts by the same microtubule-stabilizing mechanism as the FDA-approved cancer drug paclitaxel (Taxol™). These drugs prevent cancer cell proliferation by over-stabilizing specialized microtubules involved in the separation of chromosomes during the process of cell division. However, the Penn researchers previously demonstrated that EpoD, unlike paclitaxel, readily enters the brain and so may be useful for treating AD and related disorders.

After three months of receiving EpoD, additional tau clumps did not form in the brains of the aged AD mice, and nerve-cell function was increased compared to the AD mice that did not receive drug. What’s more, the EpoD-treated mice showed improvements in learning and memory. Importantly, the doses of EpoD that resulted in these benefits were much lower than had previously been used in Phase II clinical testing of EpoD in cancer patients. The investigators observed no side-effects — including the suppression of the immune system and peripheral nerve damage -- in the transgenic mice that received EpoD. _UPennNews

Most approaches to treating Alzheimer's dementia aim to either affect the levels of neurotransmitters in the brain -- particularly acetylcholine -- or to decrease accumulation of amyloid beta protein.

The idea of over-stabilising neurotubules to prevent tau tangles from forming in early stage Alzheimer's is an intriguing approach, and dates to earlier studies attempting to discover the true etiological origins of Alzheimer's. More from a 2011 study published in The Journal of Neuroscience:

Alzheimer's disease (AD) pathology is characterized by senile plaques (SPs) and neurofibrillary tangles (NFTs) (Selkoe, 2001). SPs are extracellular deposits of amyloid-β (Aβ), a 3–4 kDa peptide derived from proteolytic cleavage of the amyloid precursor protein (APP) by β-site APP cleavage enzyme 1 (BACE) (Hussain et al., 1999; Sinha et al., 1999; Vassar et al., 1999; Yan et al., 1999) and the presenilin (PS)-containing γ-secretase complex (De Strooper et al., 1998; Wolfe et al., 1999). NFTs are intracellular accumulations of hyperphosphorylated tau (Lee et al., 2001). About 5% of AD cases are linked to pathogenic mutations in APP, PS1, or PS2 genes (Selkoe, 2001). Tau gene mutations are pathogenic for familial frontotemporal lobar degeneration characterized by tau pathology without SPs, indicating that tau abnormalities alone cause neurodegenerative disease (Lee et al., 2001). _Journal of Neuroscience 25 May 2011, 31(21): 7691-7699; doi: 10.1523/​JNEUROSCI.6637-10.2011

Note that researchers are still attempting to unravel the apparent multiple strings of causation involved in Alzheimer's Disease (AD) and similar neurodegenerative diseases of the brain.

The new research involving microtubule stabilisation, was performed in transgenic mice, meaning that results in human populations using such treatments may be quite different. The fact that both amyloid placques and tau tangles are seen in pathological brain specimens from AD patients suggests that more than one treatment approach may ultimately be required for many, if not most AD sufferers.

Cross-posted from Al Fin blog

Progress on Two Important SENS Anti-Ageing Themes

Aging Damage	Discovery	SENS Solution
Cell loss, tissue atrophy	19551	Stem cells and tissue engineering (RepleniSENS)
Nuclear [epi]mutations (only cancer matters)	19592, 19823	Removal of telomere-lengthening machinery (OncoSENS)
Mutant mitochondria	19724	Allotopic expression of 13 proteins (MitoSENS)
Death-resistant cells	19655	Targeted ablation (ApoptoSENS)
Tissue stiffening	19586, 19817	AGE-breaking molecules (GlycoSENS); tissue engineering
Extracellular aggregates	19078	Immunotherapeutic clearance (AmyloSENS)
Intracellular aggregates	19599	Novel lysosomal hydrolases (LysoSENS)

The "seven pillars of SENS anti-aging strategies" are shown in the table above, with a timeline of the discovery of their importance shown in the image below.

Important progress has recently been made on two of the pillars of SENS: Correcting for mutant mitochondria, and an improved clearing of cellular junk.

First, correcting human mitochondrial mutations:

Researchers at the UCLA stem cell center and the departments of chemistry and biochemistry and pathology and laboratory medicine have identified, for the first time, a generic way to correct mutations in human mitochondrial DNA by targeting corrective RNAs, a finding with implications for treating a host of mitochondrial diseases. Mutations in the human mitochondrial genome are implicated in neuromuscular diseases, metabolic defects and aging. There currently are no methods to successfully repair or compensate for these mutations, said study co-senior author Dr. Michael Teitell, a professor of pathology and laboratory medicine and a researcher with the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA.

Between 1,000 and 4,000 children per year in the United States are born with a mitochondrial disease and up to one in 4,000 children in the U.S. will develop a mitochondrial disease by the age of 10, according to Mito Action, a nonprofit organization supporting research into mitochondrial diseases. In adults, many diseases of aging have been associated with defects of mitochondrial function, including diabetes, Parkinson's disease, heart disease, stroke, Alzheimer's disease and cancer.

"I think this is a finding that could change the field," Teitell said. "We've been looking to do this for a long time and we had a very reasoned approach, but some key steps were missing. Now we have developed this method and the next step is to show that what we can do in human cell lines with mutant mitochondria can translate into animal models and, ultimately, into humans."

The study appears March 12, 2012 in the peer-reviewed journal Proceedings of the National Academy of Sciences. _esciencenews

More at the link.

Next, clearing cellular trash aggregates:

A University of Michigan cell biologist and his colleagues have identified a potential drug that speeds up trash removal from the cell's recycling center, the lysosome.

The finding suggests a new way to treat rare inherited metabolic disorders such as Niemann-Pick disease and mucolipidosis Type IV, as well as more common neurodegenerative diseases like Alzheimer's and Parkinson's, said Haoxing Xu, who led a U-M team that reported its findings March 13 in the online, multidisciplinary journal Nature Communications.

"The implications are far-reaching," said Xu, an assistant professor of molecular, cellular and developmental biology. "We have introduced a novel concept—a potential drug to increase clearance of cellular waste—that could have a big impact on medicine." _UMich News

More at the link.

Both of these developments will require a number of years to perfect and shape into useful therapies. But as noted, improved therapies in either domain would provide hope for slowing the ageing process, and for treating many of the degenerative scourges of human existence.

The SENS Foundation has worked to promote research in the seven areas pictured above. And at least partially due to the efforts of SENS, more researchers and funding agencies are picking up the same themes.

Cross-posted from Al Fin blog

Unconventional Brain Modifications

A team of neuroscientists had discovered a genetic manipulation which provides a long term increase in brain neurogenesis in mice, and which appears to boost learning and reduce anxiety and depression.

...genetic deletion of neurofibromin (Nf1), a tumor suppressor with RAS-GAP activity, in adult NPCs enhanced DG proliferation and increased generation of new neurons in mice. Nf1 loss-associated neurogenesis had the functional effect of enhancing behavioral responses to subchronic antidepressants and, over time, led to spontaneous antidepressive-like behaviors. Thus, our findings establish an important role for the Nf1-Ras pathway in regulating adult hippocampal neurogenesis, and demonstrate that activation of adult NPCs is sufficient to modulate depression- and anxiety-like behaviors. _Journal of Neuroscience

More from ScienceDaily news service:

The researchers found that the test group mice formed more neurons over time compared to controls, and that young mice lacking the Nf1 protein required much lower amounts of anti-depressants to counteract the effects of stress. Behavioral differences between the groups persisted at three months, six months and nine months. "Older mice lacking the protein responded as if they had been taking antidepressants all their lives," said Dr. Parada.

"In summary, this work suggests that activating neural precursor cells could directly improve depression- and anxiety-like behaviors, and it provides a proof-of-principle regarding the feasibility of regulating behavior via direct manipulation of adult neurogenesis," Dr. Parada said. _SD

This type of genetic manipulation will necessarily require further development before it is suitable for use in humans. In particular, it will have to be both reversible, and adjustable in effect.

The increase in hippocampal neurons also suggests the potential for augmenting learning ability in the altered mice over their full lifetimes.

Another interesting brain manipulation studied recently, is the use of the hallucinogenic drug LSD (lysergic acid diethylamide) to aid alcoholics in overcoming their addiction to ethanol. LSD has previously been used effectively to reduce cancer associated pain in terminal cancer patients, as well as to reduce or eliminate the fear of death in terminal cancer patients.

Here is more on a recent meta-analysis of the use of LSD for treating alcohol dependency:

Krebs and Johansen set out to independently extract data from previous randomized, controlled clinical trials, pooling their results. They identified six eligible trials, all carried out in the late 1960s and early 1970s. These included 536 participants, the vast majority of whom were male in-patients enrolled in alcohol-focused treatment programs. Individuals with a history of schizophrenia or psychosis were excluded from the original trials. The control conditions included low-dose LSD, stimulants, or non-drug control conditions. Each trial used clearly defined treatment-independent and standardized methods to assess outcomes on alcohol misuse.

While the experiments varied in the dosage used and the type of placebo physicians administered to patients, LSD had a beneficial effect on alcohol misuse in every trial. On average, 59 percent of LSD patients and 38 percent of control patients were improved at follow-up using standardized assessment of problem alcohol use. There was also a similar beneficial effect on maintained abstinence from alcohol. The positive effects of a single LSD dose -- reported both in these and in other, non-randomized trials -- lasts at least six months and appears to fade by 12 months. _ScienceDaily

Full study in Journal of Psychopharmacology (PDF)

Other hallucinogenic drugs besides LSD which may prove to have beneficial clinical uses include psilocybin, ketamine, and marijuana.

The human brain is an incredibly complex and dynamic organ. We should not be surprised when such a complex device sometimes "malfunctions." And we should maintain relatively open minds when in pursuit of ways to stabilise and improve brain function.

We are playing for very high stakes.

New Experimental Drug Offers Hope for Early Stroke Treatment

Number of deaths for leading causes of death
Heart disease: 599,413
Cancer: 567,628
Chronic lower respiratory diseases: 137,353
Stroke (cerebrovascular diseases): 128,842
Accidents (unintentional injuries): 118,021
Alzheimer's disease: 79,003
Diabetes: 68,705
Influenza and Pneumonia: 53,692
Nephritis, nephrotic syndrome, and nephrosis: 48,935
Intentional self-harm (suicide): 36,909 _CDC US Leading Causes of Death

As shown above, stroke -- cerebrovascular accident (CVA) -- is the 4th ranking cause of death in the US. Besides mortality, there is also significant morbidity and disability associated with stroke worldwide.

Recent research at Toronto Western Hospital provides reason to hope for better drug treatments for stroke in the near future. The researchers tested a new type of drug -- a PSD-95 inhibitor -- in primates, in an acute stroke setting. Some of their results are pictured below.

A phase 2 clinical trial in humans was also recently completed in Ontario.

Nature

In a series of experiments, Michael Tymianski and colleagues at Toronto Western Hospital in Ontario, Canada, replicated the effects of stroke in macaques before intravenously administering a PSD-95 inhibitor, or a placebo. PSD-95 inhibitors interfere with the process that triggers cell death when the brain is deprived of oxygen.

To test its effectiveness the team used MRI to measure the volume of damaged brain for 30 days following the treatment, and conducted behavioural tests at various intervals within this time.

Monkeys treated with the PSD-95 inhibitor one hour after stroke had 55 per cent less damaged tissue in the brain after 24 hours and 70 per cent less after 30 days, compared with those that took a placebo. These animals also did better in behavioural tests. Importantly, the drug was also effective three hours after stroke.

...An early stage clinical trial in humans, run by firm NoNO in Ontario has also seen positive results. _NewScientist

Nature study abstract

PSD-95 Overview

PSD-95 complex as drug target for antidepressant development

The Role of PSD-95 and Cypin in Morphological Changes in Dendrites Following Sublethal NMDA Exposure Interesting abstract providing information on underlying factors involved.

This is a line of treatment which has been obvious for decades, but which has lacked the proper basic science backing up until now. Although PSD-95 inhibitors will not prevent all brain damage from occurring in stroke, nor will they restore damaged brain to normal function afterward, they do seem to limit the amount of damage that occurs, for each stroke.

It is a type of stop-gap measure, meant to prolong relative normal function as long as possible. More optimal developments for the future will involve better preventive measures and ways to rejuvenate damaged brain after the insult occurs. Full spectrum medical care will eventually involve all avenues of treatment, prevention, and restoration.

Good News on the Alzheimer's Front

The number of Alzheimer’s victims worldwide is expected to double every 20 years... MIT neuroscientists have shown that an enzyme overproduced in the brains of Alzheimer’s patients creates a blockade that shuts off genes necessary to form new memories. Furthermore, by inhibiting that enzyme in mice, the researchers were able to reverse Alzheimer’s symptoms.

The finding suggests that drugs targeting the enzyme, known as HDAC2, could be a promising new approach to treating the disease, which affects 5.4 million Americans.

Histone deacetylases (HDACs) are a family of 11 enzymes that control gene regulation by modifying histones — proteins around which DNA is spooled, forming a structure called chromatin. When HDACs alter a histone through a process called deacetylation, chromatin becomes more tightly packaged, making genes in that region less likely to be expressed.

HDAC inhibitors can reverse this effect, opening up the DNA and allowing it to be transcribed.

In previous studies, Tsai had shown that HDAC2 is a key regulator of learning and memory. In the new study, her team discovered that inhibiting HDAC2 can reverse Alzheimer’s symptoms in mice._MIT

As the populations of the developed and emerging nations grow progressively older, the number of Alzheimer's sufferers -- and sufferers of other debilitating diseases of old age -- threaten to cripple these societies. Affordable means of preventing and treating dementias and other disabling diseases of senescence could make the difference between prosperity or poverty for many nations. The recent MIT discovery may be an important step forward in this regard.

... the team subsequently showed that using RNAi to reduce HDAC2 build up in the hippocampus of a mouse neurodegenerative disease model removed this repression, reinstated neuronal structural and synaptic plasticity, and eradicated neurodegeneration-associated memory deficits. Li-Huei Tsai, Ph.D., and colleagues report their findings in Nature in a paper titled “an epigenetic blockade of cognitive functions in the neurodegenerating brain.”

Epigenetic modifications in the nervous system that are mediated by histone acetylation have been unequivocally associated with facilitating learning and memory, the researchers state. Multiple studies have in addition reported that reduced histone acetylation is associated with cognitive decline in animal models of neurodegeneration including AD.

To further investigate the role of HDAC2 in neurodegeneration-related cognition, the team looked at levels of the enzyme in CK-p25 mice. These animals can be induced to overexpress p25, in the forebrain. p25 is a truncated version of p35 and is implicated in a range of neurodegenerative diseases. Their studies showed that animals induced to overexpress p25 demosntrated significant increases in HDAC2 in neuronal nuclei, specifically hippocampal area CA1 but not CA3 or the dentate gyrus, and also in the prefrontal cortex. In contrast, levels of the HDAC1 and HDAC3, were not changed.

The researchers then moved on to carry out chromatin immunopreciptation studies to assess the functional consequences of HDAC2 elevation, primarily in a range of known HDAC2 targets that have been shown to be downregulated in human AD brains, including learning- and memory-related genes, and those involved in synaptic plasticity. They found elevated HDAC2 enrichment at the majority of these genes induced CK-p25 hippocampus, whereas again, HDAC1 and HDAC3 binding wasn’t affected. “Interestingly, in agreement with previous reports showing that HDAC2 can also bind to a gene’s coding region, we also found HDAC2 more abundantly bound to the coding sequence of the same genes,” they note. _GenengNews

The researchers found that in mice with Alzheimer’s symptoms, HDAC2 (but not other HDACs) is overly abundant in the hippocampus, where new memories are formed. HDAC2 was most commonly found clinging to genes involved in synaptic plasticity — the brain’s ability to strengthen and weaken connections between neurons in response to new information, which is critical to forming memories. In the affected mice, those genes also had much lower levels of acetylation and expression.

“It’s not just one or two genes, it’s a group of genes that work in concert to control different phases of memory formation,” Tsai says. “With such a blockade, the brain really loses the ability to quickly respond to stimulation. You can imagine that this creates a huge problem in terms of learning and memory functions, and perhaps other cognitive functions.”

The researchers then shut off HDAC2 in the hippocampi of mice with Alzheimer’s symptoms, using a molecule called short hairpin RNA, which can be designed to bind to messenger RNA — the molecule that carries genetic instructions from DNA to the rest of the cell.

With HDAC2 activity reduced, histone acetylation resumed, allowing genes required for synaptic plasticity and other learning and memory processes to be expressed. In treated mice, synaptic density was greatly increased and the mice regained normal cognitive function. _MIT

The MIT researchers have utilised a number of different advances in cell and molecular biology to make these discoveries. As scientists close in on the discovery of meaningful interventions in destructive pathological processes, the importance of pre-existing replicated "off the shelf" research grows.

This is good news for all mice who suffer from Alzheimer's. Now, scientists must confront the immense government-made mine field and obstacle course which obstructs modern efforts to affordably develop life saving interventions in the biomedical fields, for humans. In this sense -- as in many others -- government is the greatest enemy of the future.

Cross-posted from Al Fin

Tissue Repair Gel Scaffold: Hope for Healing Cardio-Infarction

UCSD scientists have developed an injectable gel to reinvigorate damaged heart tissue, after a heart attack. Heart failure subsequent to myocardial infarction is a significant cause of death in adults of advanced nations. Tissue replacement and revitalisation treatments such as this, promise to add healthy years to the lives of tens of millions of people, worldwide.

Researchers claim to have developed a new injectable hydrogel which they say could be used to repair tissue damaged by heart attacks.

A team at the University of California, led by Karen Christman, hopes to bring the gel to clinical trials within the next year, the latest edition of Journal of the American College of Cardiology reported.

Therapies like the hydrogel would be a welcome development, Christman explained, since there are an estimated 785,000 new heart attack cases in the US each year, with no established treatment for repairing the resulting damage to cardiac tissue.

The hydrogel is made from cardiac connective tissue that is stripped of heart muscle cells through a cleansing process, freeze-dried and milled into powder form, and then liquefied into a fluid that can be easily injected into the heart.

Once it hits body temperature, the liquid turns into a semi-solid, porous gel that encourages cells to repopulate areas of damaged cardiac tissue and to preserve heart function, according to Christman.

The hydrogel forms a scaffold to repair the tissue and possibly provides biochemical signals that prevent further deterioration in the surrounding tissues. _HinduBusinessLine

Study abstract
Abstract of earlier study

This type of cellular replacement and tissue replacement is important if we are to be able to stretch out the useful lifetimes of genetically flawed bodies. Prevention of disease is better than treatment. Genetic re-design to reduce vulnerabilities may be best of all. Stay tuned.

Previously published on Al Fin blog

We are on the road to re-growth of damaged tissues and entire organs. Development of the proper type of scaffold for organ and tissue growth is crucial.

A Brain Zapping Method of Removing Unwanted Nerve Connections

Scientists at the University of Western Australia have devised an intriguing method of removing unwanted neural connections in mice. Whether or not this procedure is directly applicable to humans, it opens a world of possibilities for improving the mental lives of a wide range of persons at every stage of life, from early onset schizophrenia through the brain maladaptations of senescence.

One of the pillars of Aubrey de Grey's Sens approach to anti-ageing is the removal of malfunctioning cells in the body. There is an analogous need in the brains of many individuals to remove malfunctioning or excess nerves and nerve connections, to optimise or improve brain functioning. Here is more on the experiments in mouse brains:

Jennifer Rodger from the University of Western Australia in Crawley and colleagues have found that stimulating the brain at intensities lower than would make a neuron fire can remove unwanted neural connections in mice.

As children, our brains produce too many connections between cells. As we develop, some connections are pruned away while others are strengthened. Inept pruning has been implicated in schizophrenia.

Rodger's team used genetically modified mice with abnormal connections in an area of the brain called the superior colliculus (SC), which is involved in motion detection. In these mice, 90 per cent of the axons in the SC had extended into the wrong areas. These bad connections make it difficult for the rodents to follow moving objects in their line of sight.

Rodger used low-intensity, pulsed magnetic field stimulation (PMF) on the rodents' SC for 10 minutes a day over two weeks. It is thought that PMF is too weak to make healthy neurons fire. But after treatment, tissue analysis showed that only 45 per cent of the abnormal axons were still there. "The axons that weren't in the right place were wiped out," says Rodger. After treatment the mice were also better at tracking objects.

"PMF is awakening unwanted connections, so the brain can detect and remove them," says Rodger.

Unwanted neurons generally express high levels of a specific NMDA glutamate receptor. According to Rodger, this makes them sensitive to changes in electrical activity and so even low-intensity pulses can activate these neurons.

NMDA receptors send out signals that trigger the recruitment of two chemicals called nitric oxide and brain-derived neurotrophic factor (BDNF), which help remove abnormal circuitry in healthy brains. Indeed, modified mice given PMF expressed higher levels of both chemicals, while only minor changes were found in healthy mice or those given a sham procedure (The FASEB Journal, DOI: 10.1096/fj.11-194878).

"I think it is a very promising avenue for treatment of nervous system disorders that involve abnormally abundant and inaccurate connections," says Rodger. _NewScientist

The brain is in a constant state of plasticity and re-shaping throughout life. But the brain often ends up in malfunctioning or maladaptive states which can be difficult to re-shape, without outside assistance. Part of the problem may lie in the genomics or gene expression of receptors or ion channels -- leading to consequent problems at higher levels of neuron function and the function of neuronal assemblies. Optimally, the underlying genetic or epigenetic cause would be corrected. But that isn't possible in most cases -- not yet.

In the meantime, workaround solutions such as the one discovered by the Australian researchers, may well allow for cruder fixes that can still add significantly to the quality of a person's mental existence.

The challenge in this case is to not only remove unwanted nerves or neural connections. One must also be able to stimulate growth of new neural connections in more optimal configurations.

Precious Metals vs Cancer: Platinum, Gold, and Silver

Platinum was the first precious metal to achieve recognition as an effective cancer therapy:

The first platinum based chemotherapy drug discovered by researchers was cisplatin, which forty years later continues to have applications in certain types of cancer. In that time, scientists have searched for ways to improve the anti-tumor efficacy of platinum based drugs, reducing the toxicity profile, and strengthening them against resistance by expanding the class to include several new analogues of cisplatin and putting them through clinical trials to broaden the different types of cancers against which they can be safely used. _Source

Gold has more recently been recognised to have utility in fighting cancer. Gold is being used to help locate tumours and cancer cells for radiation treatment, and is also being used in drug complexes, for its cytotoxic properties.

In the last few decades the properties of gold compounds have been of interest as potential cancer treatments. Researchers at the National University of Singapore have patented novel gold complexes for use in pharmaceuticals for the treatment of cancer.

Associate Professor Leung Pak Hing and his team have discovered that phosphine supported gold complexes have excellent anti-tumour activity and clinical trials are likely to begin in the near future.

In some cases, new technologies rely on the ability of tiny gold nanoparticles to specifically collect in a cancerous tumour by passing through the inherently leaky blood vessels attached to a tumour. So, when injected into a patient, there is a means by which a potent anti-cancer compound attached to a gold nanoparticle, can be directly and accurately delivered to a tumour whilst avoiding healthy body tissue. Such an effective drug delivery mechanism with reduced toxicity is considered to be a major step-forward. Why use gold as the delivery mechanism? Well gold has a major advantage in being a very biocompatible metal. For example, colloidal gold has been safely used for over 70 years to treat rheumatoid arthritis, and many hundreds of years as a dental restoration. _AzoNano

Even more recently, silver is being seen as a potentially effective anti-cancer material.

Previous studies have hinted that silver compounds could also kill cancer cells. So Charlotte Willans from the University of Leeds, UK, and colleagues subjected silver to the same treatment as platinum to see if they could make an effective cancer drug.

The team attached different types of carbene ligands to the silver atoms before incubating varying concentrations of the compound with breast and colon cancer cells for six days.

The silver complexes proved to be as effective as cisplatin in attacking both types of cancer cells. Complexes containing a ligand which had two bonds were more effective than those with a single bond, probably because they are more stable - meaning the compound breaks down more slowly and is active for longer (Dalton Transactions, DOI: 10.1039/C2DT12399A).

Crucially, silver is less toxic to normal cells than platinum. Willans says it is an important step in the quest for effective, non-toxic cancer treatments. _NewScientist

More on the use of silver to treat cancer

The use of precious metals to treat cancer is one more reason to value them for their intrinsic worth. In developed societies, cancer is responsible for more lost years of life than virtually any other disease.

Important New Insights into Alzheimer's Disease from Cultured Adult Induced Stem Cells from Alzheimer's Patients

When you take skin cells from an Alzheimer's patient, and turn them into neurons in culture, you can study these "Alzheimer's neurons" in detail in the lab. This ability to work with cultured human Alzheimer neurons from induced stem cells, on a day to day basis, will give scientists an intimate familiarity with the genetic and biochemical differences which lead to the pathological changes in the disease. And none too soon, because as western societies grow older, Alzheimer's is threatening to bankrupt their social medicine services.

The feat, published in the January 25 online edition of the journal Nature, represents a new and much-needed method for studying the causes of AD, a progressive dementia that afflicts approximately 5.4 million Americans. More importantly, the living cells provide an unprecedented tool for developing and testing drugs to treat the disorder.

“We’re dealing with the human brain. You can’t just do a biopsy on living patients,” said Goldstein. “Instead, researchers have had to work around, mimicking some aspects of the disease in non-neuronal human cells or using limited animal models. Neither approach is really satisfactory.”

Goldstein and colleagues extracted primary fibroblasts from skin tissues taken from two patients with familial AD (a rare, early-onset form of the disease associated with a genetic predisposition), two patients with sporadic AD (the common form whose cause is not known) and two persons with no known neurological problems. They reprogrammed the fibroblasts into induced pluripotent stem cells (iPSCs) that then differentiated into working neurons.

The iPSC-derived neurons from the Alzheimer’s patients exhibited normal electrophysiological activity, formed functional synaptic contacts and, critically, displayed tell-tale indicators of AD. Specifically, they possessed higher-than-normal levels of proteins associated with the disorder.

With the in vitro Alzheimer’s neurons, scientists can more deeply investigate how AD begins and chart the biochemical processes that eventually destroy brain cells associated with elemental cognitive functions like memory. Currently, AD research depends heavily upon studies of post-mortem tissues, long after the damage has been done.

“The differences between a healthy neuron and an Alzheimer’s neuron are subtle,” said Goldstein. “It basically comes down to low-level mischief accumulating over a very long time, with catastrophic results.”

The researchers have already produced some surprising findings. “In this work, we show that one of the early changes in Alzheimer’s neurons thought to be an initiating event in the course of the disease turns out not to be that significant,” Goldstein said, adding that they discovered a different early event plays a bigger role.

The scientists also found that neurons derived from one of the two patients with sporadic AD exhibited biochemical changes possibly linked to the disease. The discovery suggests that there may be sub-categories of the disorder and that, in the future, potential therapies might be targeted to specific groups of AD patients.

Though just a beginning, Goldstein emphasized the iPSC-derived Alzheimer’s neurons present a huge opportunity in a desperate fight. _UCSD

This research is geared specifically toward Alzheimer's disease research, since Alzheimer's patients are the donours of the original cells being used. But the same approach can be used to culture a wide range of induced cell types, from patients with a wide range of disease types. In other words, this is just the beginning of a beautiful approach to bringing the full dynamics of human diseases into the laboratory for thorough study.

There is no way of predicting what possibilities may arise from this research over the long run.

3 Dimensional Bio-Cell Printing: Future Tissue & Organ Replacements

An optimized 3D inkjet printing process is demonstrated for structuring alginate into a tissue-like microvasculature capable of supporting physiological flow rates. Optimizing the reaction at the single-droplet level enables wet hydrogel droplets to be stacked, thus overcoming their natural tendancy to spread and coalesce. Live cells can be patterned using this process and it can be extended to a range of other hydrogels. _Advanced Materials

The dream is to be able to rapidly grow replacement tissues and organs, to allow for easy autologous replacement for a wide range of clinical reasons and circumstances -- including life extension regenerative treatments.

...Thus, it would take just under 2 hours to print a 1 cm thick tissue precursor graft and just over 5 h 30 to print a 3 cm thick kidney precursor. _Advanced Materials PDF

Swiss scientists are using a special inkjet printer to assemble three dimensional living constructs that resemble living tissues. They are still in the early stages of the research, but are achieving some interesting results.

They are working on a technique that should eventually allow them to “print” living constructs resembling human tissues in which cells can develop and interact in a coordinated and physiological manner. Their research results have recently been published in the scientific journal Advanced Materials.

“We have not yet created tissue, strictly speaking,” explains Professor Jürgen Brügger, head of EPFL’s Microsystems 1 Laboratory. “At this stage, we have essentially studied a way in which to structure biological materials in three dimensions; this research will improve cell culture and then will eventually be used as a base for creating tissues.”

...To make up a coherent whole, the cells need an environment that provides the right kinds of signals that induce very specific behavior in each of the cells – proliferation, migration, differentiation or death. In natural tissues, these signals come from molecules that make up a complex extracellular matrix (ECM). By studying the connections and communications taking place between cells and between cells and ECM molecules, the scientists were able to reconstruct this matrix and thus create a new kind of biological ink.

On a technical level, the researchers from EPFL’s two Microsystems Laboratories – under the leadership of professors Jürgen Brugger and Philippe Renaud – focused on developing a gel that could be used as a base from which the tissue could be constructed, as well as a strategy for printing droplets.

...Even though it will still be quite some time before tissue can be constructed, this technology could lead to very promising applications on the medium term. “ An exiting avenue would be to develop 3D constructs that function like human tissues and could be used as models for testing new drugs,” says Lutolf. “This is not only very interesting in a biological sense, but could also reduce the need for animal testing.” _Physorg

Learning to create life-like 3 dimensional cell cultures for research, and learning to create 3-D lab-made living tissues for replacement, are not quite the same things. But the two lines of research are likely to borrow from and contribute to each other, extensively.

This research used fibroblasts. Future research is likely to use a variety of stem cells and other precursor cells for various cell types.

Non-fluorescent NIH 3T3 fibroblasts were used in this printing as to be compatible with the fluorescent Live-Dead assay. The cells were suspended in culture medium supplemented with 0.8% wt. non-fluorescent alginate at a concentration of 1x10 6 mL -1 . Cells were inkjet printed onto 2% wt. gelatin substrates prepared with 0.9% wt. NaCl and 10 mM CaCl2, prepared in a 96-well plate. All cells were incubated for 4h before Live-Dead staining. _Advanced Materials

Living More of Your Time: Enjoying and Mastering Alcohol

A person may "live" between 70 and 80 years, but only truly experience a relatively few years of life. After subtracting the time a person spends either sleeping, intoxicated, in childhood / adolescence, or in declining senescence, very few optimally productive years of time may be left.

An herbal chemical has been discovered which may well allow us to reduce our impairment from alcohol intoxication, giving us more time to appreciate, enjoy, and profit from our lives.

Led by Jing Liang from the University of California, researchers began looking at different herbs that have natural anti-alcohol properties. They found descriptions of anti-alcohol properties of the Asian tree Hovenia dulcis that dated back to 659. These descriptions listed it as a prime hangover remedy.

The main ingredient in Hovenia dulcis is known as dihydromyricetin, or DHM. The team of researchers used rats to test out the effects. Rats react similar to humans when it comes to the effects of alcohol so they are a perfect candidate.

The rats were given the human equivalent of 15-20 beers in a time frame of under two hours. As expected, the rats passed out drunk and lost the ability to flip themselves over when placed on their back. Within an hour, the effects of the alcohol started to wear off and they were able to again control their bodies.

When the rats were given the same alcohol with a shot of the DHM, they still eventually lost the ability to flip over but it took a longer time period and they were able to recover from the effects in about 15 minutes.

The effects of the DHM went beyond that though. Two days after the alcohol consumption, the rats that were given the DHM showed less signs of hangover symptoms such as anxiety and seizures.

The other noted result was the reduction in addiction. When the rats were allowed to drink freely, they would gradually start consuming more. However, those rats that had received the DHM did not increase consumption. _MedicalXpress

The promise of this herb goes far beyond a treatment for alcohol addiction. It promises to give us back a great deal of the time that we voluntarily sacrifice to alcohol -- and the aftereffects of alcoholic indulgence.

How many bad choices do people make under the influence of alcohol, which lead to further destruction of our time and our lives -- as well as the premature ending of many innocent lives?

Earlier we looked at ways that we may safely reduce our sleeping time -- thus adding years to our lives. If we can also reduce much of the time wasted by intoxicants, we may well have added significantly more profitable time to our lives.

Life extension is about more than simply "living" more years. It is also about truly living the time that you are alive.

http://www.jneurosci.org/content/32/1/390.abstract: Article abstract link

Young Stem Cells In Old Mice Increased Lifespan

A special breed of mice lived up to three times longer than normal after University of Pittsburgh researchers injected them with stem cells from younger, healthy mice, according to a study being published today in the journal Nature Communications.

Working with mice that are bred to die prematurely, Pitt researchers led by Johnny Huard and Laura Niedernhofer dramatically increased the animals' lifespans by injecting them in the abdomen with young animals' muscle stem cells. _Post-Gazette

Keep in mind that this research was done in a special breed of mouse that is programmed to have a shorter lifespan. Additional research will be required to determine if normal ageing mice can benefit from similar treatment.

"We wanted to see if we could rescue these rapidly aging animals, so we injected stem/progenitor cells from young, healthy mice into the abdomens of 17-day-old progeria mice," Dr. Huard said. "Typically the progeria mice die at around 21 to 28 days of age, but the treated animals lived far longer – some even lived beyond 66 days. They also were in better general health."

As the progeria mice age, they lose muscle mass in their hind limbs, hunch over, tremble, and move slowly and awkwardly. Affected mice that got a shot of stem cells just before showing the first signs of aging were more like normal mice, and they grew almost as large. Closer examination showed new blood vessel growth in the brain and muscle, even though the stem/progenitor cells weren't detected in those tissues.

In fact, the cells didn't migrate to any particular tissue after injection into the abdomen.
"This leads us to think that healthy cells secrete factors to create an environment that help correct the dysfunction present in the native stem cell population and aged tissue," Dr. Niedernhofer said. "In a culture dish experiment, we put young stem cells close to, but not touching, progeria stem cells, and the unhealthy cells functionally improved." _MedXpress

Stem cells can conceivably be used for many purposes, in the treatment of ageing. In the case of the above research, the stem cells apparently secreted some type of hormonal growth factor which was lacking in the progeria mice.

But in future, more sophisticated uses of stem cells to treat ageing, stem cells will be used for tissue replacement, organ regeneration and replacement, humoral factor replacement, and probably other uses not yet discovered.

A Lesson in Basic Gene Expression

Directions for making proteins are encoded in the DNA sequences of genes, which reside on chromosomes in the nucleus of each cell. But for proteins to be made, a gene’s DNA code must be copied, or transcribed, onto mRNA molecules, which migrate from the nucleus and into the cytoplasm where the cell’s protein-making machinery is located. For as long as it exists, an mRNA molecule can act as a template for making copies of a protein. So scientists have long suspected that cells must have ways for degrading mRNAs when, for example, a protein starts accumulating to harmful levels. “The cell somehow decides to destroy its mRNA on cue, but nobody knew how this happens,” said Dr. Singer. _EinsteinNews

Gene Expression Image
Understanding gene expression is one of the keys to the discovery of how to live much longer and healthier lives. The basic outline of gene expression has been known for several decades, but the details of control and timing of the complex networks of gene expression are just being exposed.

Scientists at Albert Einstein College of Medicine recently made a basic discovery in the control of messenger RNA lifespan, which may help to unlock one of the important doors to understanding.

When genes are transcribed, a part of the gene called the promoter region has the job of switching on the gene so that DNA will be copied into mRNA. The Einstein scientists found that the promoter regions of the SWI5 and CLB2 genes do something else as well: they recruit a protein called Dbf2p, which jumps onto mRNA molecules as they’re being synthesized.

These mRNAs—transcribed from the SWI5 and CLB2 genes and bearing the Dbf2p protein—make their journey from the nucleus into the cytoplasm. Here a protein called Dbf20p joins Dbf2p aboard the mRNA molecules—and the two proteins together call for the molecules’ precipitous decay.

“Our findings indicate that genes making proteins whose levels must be carefully controlled contain promoter regions that sentence their mRNA molecules to death even as the mRNA is being born,” said Dr. Singer. “The promoter regions do that by ‘marking’ the newly made mRNA with the protein Dbf2p—the common factor between mRNA synthesis and its ultimate decay. Dbf2p stays attached to the mRNA from its birth and then, responding to a signal indicating that no more protein should be made, orders mRNA’s destruction.” _EinsteinNews

You see, as long as the messenger RNA stays around in the cytoplasm, it will keep binding to ribosomes, and continue to produce its protein. This is not what the cell wants, in general, since the relative quantities of different proteins are maintained in a healthy balance.

The application of this discovery to life extension is not immediately apparent to the casual reader. And yet as we come to understand the build-up of imbalances within cells which accompany the ageing process, we are likely to find multiple ways in which this particular system can go wrong, and contribute to degenerative changes.

The better we understand this complex dance of molecules, the better will be our solutions to the problems that occur when the complex system begins to break down. Eventually, we will probably want to re-design some of these sub-systems in ways to make them more robust.

PDF of actual study, published in Cell

Salk Researchers Take a Stab at New Approach to Alzheimer's Tx

At present, there are few drugs that improve the memory deficits associated with normal aging and none that prevent cognitive decline in chronic neurodegenerative conditions such as Alzheimer's disease (AD). Except for the rare cases of familial AD, the cause of AD is not known, but the disease is highly correlated with aging, a process involving a wide variety of physiological changes. Therefore, it is likely that the cells in the aging brain are compromised not from a single cause but from the convergence of multiple insults. However, the currently most widely used approach to drug discovery is to identify a single molecular target and then make a drug that alters this target [1]. Unfortunately, drugs for AD that were developed through this approach have all failed in clinical trials, perhaps because one target is not sufficient or because the targets are also critical for normal brain function so that their inactivation results in toxicity. Therefore, a different approach to drug discovery for AD is needed [2], [3]. _PLoS

Currently, the major drug discovery paradigm for neurodegenerative diseases is based upon high affinity ligands for single disease-specific targets. For Alzheimer's disease (AD), the focus is the amyloid beta peptide (Aß) that mediates familial Alzheimer's disease pathology. However, given that age is the greatest risk factor for AD, we explored an alternative drug discovery scheme that is based upon efficacy in multiple cell culture models of age-associated pathologies rather than exclusively amyloid metabolism. Using this approach, we identified an exceptionally potent, orally active, neurotrophic molecule that facilitates memory in normal rodents, and prevents the loss of synaptic proteins and cognitive decline in a transgenic AD mouse model. _PLoS

The "amyloid hypothesis" has not been a productive research pathway for finding cures for Alzheimer's -- at least not yet. Salk researchers chose to develop a new series of pharmacological agents based upon the neuroprotective action of the herb curcumin. Curcumin does not enter the brain in high enough concentrations to reverse the symptoms of Alzheimer's Disease, once the disease has progressed to the symptomatic stage. But the new Salk molecules, based upon curcumin's effect, are able to reverse some of the signs of neurodegeneration in aging animal brains.

If the new drug -- J147 -- proves to be effective, and is as safe as curcumin itself, it is likely to become the prototype for a new approach to treating neurodegeneration of aging in general, and Alzheimer's in particular.

H/T Gizmag