Breakthroughs in Stroke, Brain Cancer, and Tissue Engineering

We may dream of discovering a "fountain of youth," a magic bullet treatment to achieve immortality with just a single elixir, fruit, capsule, or injection. But the modern reality of the anti-aging effort is that, for now, we must attack each killer disease individually.

An impressive new treatment for cerebrovascular accidents -- brain strokes -- was developed at the University of Manchester.

Researchers induced a stroke in the rats and the drug IL-1Ra, or a placebo for comparison, was injected under the skin. The researchers did not know which animals had been given which drug. This is a similar process to what happens in clinical trials of medicines.

The results were startling. MRI scans revealed that the rats that were given IL-1Ra up to three hours after the stroke had only about half the brain damage of the placebo group.

Professor Rothwell said: “This is the first time that we are aware of a potential new treatment for stroke being tested in animals with the same sort of diseases and risk factors that most patients have. The results are very promising and we hope to undertake further clinical studies in stroke patients soon.”

IL-1Ra works by blocking the naturally occurring protein interleukin 1. Researchers at The University of Manchester have identified that it is a key cause of brain injury following a stroke.

Interleukin 1 encourages inflammation in the area of the brain affected by stroke. This sends out signals to attract white blood cells and to switch on microglia cells in the brain. Because the barrier surrounding the brain has been weakened by the stroke the white blood cells find it easier to enter the brain. But instead of helping the inflamed area they actually kill nerve cells and worsen the injury. The increasing presence of these cells also explains why the damage in the brain gets worse over time following a stroke.

IL-1Ra also reduces the amount of damage to the blood-brain barrier following a stroke so the harmful cells can’t enter the brain. In the recent experiments IL-1Ra reduced the damage to the blood-brain barrier by 55% in healthy rats and 45% in rats with underlying health conditions. In all types of rats the drug reduced the amount of activated microglia cells by 40% compared to the placebo group. _Manchester

A similar type of anti-inflammatory therapy is also being developed to combat Alzheimer's, multiple sclerosis, traumatic brain injury, and other forms of neurodegenerative and inflammatory brain disease.

The fight against brain cancer and other solid tumours was advanced recently by the University of Tennessee Space Institute. The technique utilises a femtosecond laser to both precisely target and destroy tumours.

“Using ultra-short light pulses gives us the ability to focus in a well confined region and the ability for intense radiation,” said Parigger. “This allows us to come in and leave a specific area quickly so we can diagnose and attack tumorous cells fast.”

Once the cancerous area is precisely targeted, only the intensity of the laser radiation needs to be turned up in order to irradiate, or burn off, the tumor. This method has the potential to be more exact than current methods and to be done as an outpatient procedure replacing intensive surgery.

“Because the femtosecond laser radiation can be precisely focused both spatially and temporally, one can avoid heating up too many other things that you do not want heated,” said Parigger. “Using longer laser-light pulses is similar to leaving a light bulb on, which gets warm and can damage healthy tissue.”

The technology can be especially helpful to brain cancer victims. The imaging mechanism can non-invasively permeate thin layers of bone, such as the skull, and can help define a targeted treatment strategy for persistent cancer. The method also overcomes limitations posed by current treatments in which radiation may damage portions of healthy brain tissue. It also may overcome limitations of photodynamic therapy that has restricted acceptance and surgery that may not be an option if not all carcinogenic tissue can be removed. _UTSI

Combining the targeting function with the therapeutic heating function saves time and improves therapeutic precision, and the improved precision of targeting saves surrounding normal tissue.

Research engineers at the University of Toronto have developed a new, rapid method of tissue engineering, capable of creating 3-D layered tissues in an advanced hydrogel.

Scientists manipulate biomaterials into the micro-device through several channels. The biomaterials are then mixed, causing a chemical reaction that forms a "mosaic hydrogel"—a sheet-like substance compatible with the growth of cells into living tissues, into which different types of cells can be seeded in very precise and controlled placements.

Unique to this new approach to tissue engineering, however, and unlike more typical methods for tissue engineering (for instance, scaffolding, the seeding of cells onto an artificial structure capable of supporting three-dimensional tissue formation) cells planted onto the mosaic hydrogel sheets are precisely incorporated into the mosaic hydrogel sheet just at the time it's being created—generating the perfect conditions for cells to grow. _UToronto

This approach is likely to evolve rapidly to provide quick replacement tissues of a simpler nature, such as skin grafts. More complex tissues and organs will require sophisticated scaffolds, to allow the tissue to maintain shape and resist a variety of physical forces likely to come to bear in a variety of implant locations.

The fight against deadly diseases and ageing itself, must necessarily take on multiple forms. Humans have not, after all, conquered even the most rudimentary of enemies -- the virus. Despite our best efforts, we are still vulnerable to new outbreaks of emerging infectious diseases. And we will always be vulnerable to chance events such as accidents -- both terrestrial and cosmic.

But it is in the nature of our slightly advanced monkey selves to pursue our continued existence, as long as we can. h/t Brian Wang

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

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.

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

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.

Would You Trade Places With a Naked Mole Rat?

the naked mole rat has what could be the most extraordinary set of natural defenses ever found in a mammal. A mouse's life is short and terrible—even in the lab, with plenty of food and a steady thermostat, it lasts for just three or four years at the most. A naked mole rat shows no sign of aging until it's a quarter of a century old. Blind and plump, it skitters around in a hazmat suit of its own creation. _Slate

Naked mole rats appear impervious to radiation and carcinogens of all kinds. These naked mole rats are incredibly reluctant to get cancer. And that is not the half of it:

In 2004, Buffenstein and her students tried one of these shortcuts. They placed some mole rats in a gamma chamber and blasted their pale, pink bodies with ionizing rays. The animals were unimpressed. When I visited Buffenstein’s lab this past July, many were still alive, skittering through the plastic tubes of their basement habitat at the Barshop Institute for Longevity and Aging Studies.

Four years later, Buffenstein...infected cells from a naked mole rat with a virus designed to corrupt their nuclei with the cancer-causing genes SV40 TAg and Ras. Then she slipped those cells into a live mouse, under the skin behind its ear. If you do the same using infected material from a mouse or a rat, or even a cow or a human, the transplant quickly grows into a deadly tumor, invading nearby fat and muscle tissue. But when Buffenstein and her colleagues used cells from a naked mole-rat, nothing happened.

...Earlier this year, one of Buffenstein's graduate students tried smearing the skin of half a dozen naked mole rats with a pair of vicious carcinogens: A synthetic compound called DMBA and an inflammatory agent known as TPA. When the same toxic pairing was applied to regular Black-6 lab mice as an experimental control, a cluster of tumors popped up within weeks. Every single mouse had cancer, and every single mouse died. The naked mole rats went on skittering through their tubes.

...Her latest assault involves pouring carcinogens down the mole rats' throats in a last-ditch effort to induce liver or mammary cancer. But that may not work, either. For years, Buffenstein's laboratory Rasputins have been irradiated, poisoned, and heated up; their cells dosed with every imaginable pollutant—chemotherapies, oxidative stressors, and heavy metals—with little or no effect. "You name it," the professor says, "we tried all the kinds of toxins that are out there, and the naked mole rat seems to be very resilient and resistant."

...The very thing that makes naked mole rats so interesting to Buffenstein—an astonishing vitality that lasts for decades—only makes her research more difficult. "You're caught between a rock and a hard place, because they live so long that your grandchildren have to finish the studies you start." Still, slow science may have rich rewards, and the decisions we make today—on whether to invest in new model organisms or build out the ones we already have—are sure to have profound effects on the (human) generations to come. _Slate

The above Slate article by Daniel Engber is an excellent example of good science writing. We learn about the things that make the naked mole rat intriguing as an object of study, then we learn why the biomedical funding establishment is so biased against funding studies using naked mole rats. The life of science is full of such conflicts, which can drive scientists out of the lab entirely if they cannot learn to deal with the frustrating politics and grant grubbing.

No human would want to trade places with a naked mole rat, even if it meant living 10 times longer -- and in better health -- than the average human. But we might want some of the naked rats resistance to cancer and degenerative change.

Human gerontologists are not trying to discover the path to immortality. They are not even trying to give humans the relative advantage in life span that the naked mole rat has over other rodents. What human scientists are trying to achieve is fairly modest -- they want to find a way to delay the signs of aging for roughly seven years beyond the average:

THE TARGET What we have in mind is not the unrealistic pursuit of dramatic increases in life expectancy, let alone the kind of biological immortality best left to science fiction novels.20 Rather, we envision a goal that is realistically achievable: a modest deceleration in the rate of aging sufficient to delay all aging-related diseases and disorders by about seven years.21 This target was chosen because the risk of death and most other negative attributes of aging tends to rise exponentially throughout the adult lifespan with a doubling time of approximately seven years.22 Such a delay would yield health and longevity benefits greater than what would be achieved with the elimination of cancer or heart disease.23 And we believe it can be achieved for generations now alive.

If we succeed in slowing aging by seven years, the age-specific risk of death, frailty, and disability will be reduced by approximately half at every age. People who reach the age of 50 in the future would have the health profile and disease risk of today’s 43-year-old; those aged 60 would resemble current 53-year-olds, and so on. Equally important, once achieved, this seven-year delay would yield equal health and longevity benefits for all subsequent generations, much the same way children born in most nations today benefit from the discovery and development of immunizations.

A growing chorus of scientists agrees that this objective is scientifically and technologically feasible. How quickly we see success depends in part on the priority and support devoted to the effort. Certainly such a great goal – to win back, on average, seven years of healthy life – requires and deserves significant resources in time, talent and treasury. But with the mammoth investment already committed in caring for the sick as they age, and the pursuit of ever-more expensive treatments and surgical procedures for existing fatal and disabling diseases, the pursuit of the Longevity Dividend would be modest by comparison. In fact, because a healthier, longer-lived population will add significant wealth to the economy, an investment in the Longevity Dividend would likely pay for itself. _"TheScientist"_via_NR

Can we learn anything toward that end, from the naked mole rat? Quite possibly. But we have to be willing to put in the time and expense to learn how to transfer the lessons from that exceptional rodent to the human species.

Molecular Circuits Learn to Trigger Targeted Cancer Cell Death

Discover
An international team of researchers has learned to use micro-RNA circuits to trigger targeted cell death in HeLa cells, widely used cultured cervical cancer cells, orginally taken from a woman who died long ago. Although it is too late for this information to help Henrietta Lacks, it is possible that this approach -- or something like it -- may be used to trigger the large-scale suicide of a wide range of cancer cells eventually.

Xie has developed a genetic “logic circuit” that prompts cells to kill themselves if the levels of five molecules match those of a cancer cell. Yaakov Benenson, who led the study, says, “In the long term, the circuits’ role is to act like miniature surgeons that can identify and destroy cancer cells.” That is a very long way off, but the study is a promising step in the right direction.

Xie worked with HeLa cells, a common line of cervical cancer cells taken from a tobacco farmer called Henrietta Lacks in 1951. Since then, they have become one of the most important tools in modern medicine. Xie identified five small molecules called microRNAs that act as a signature for HeLa cells, separating them from healthy ones. Two of the microRNAs are unusually common in HeLa; three are unusually rare.

Next, Xie created five genetic switches that would only flip if their respective microRNAs were found at the right levels. The switches control a gene called Bax, an executioner that compels a cell to kill itself. If the circuit is introduced into a cell that carries the molecular signature of HeLa, all five switches flip, Bax is roused into action, and the cell automatically self-destructs.

Xie rigged his circuit so that Bax could be restrained by each of the three microRNAs found at low levels in HeLa cells. The gene would only activate if all three molecules were largely absent; any one of them could stay the executioner’s hand. Meanwhile, the two microRNAs that are common in HeLa actually lift restraints on Bax, by blocking genes that keep it in check. Again, the circuit needs high levels of both of these molecules. If either is absent, Bax is held back.

This clever set up means that all five switches must to be flipped before the executioner carries out it bloody work. The cell only dies if it meets every one of five conditions. And Xie found that his circuit worked in practice. It activated Bax at far higher levels in HeLa cells and selectively killed them while leaving other lineages of laboratory cells unharmed. _Discover

Article abstract from Science

More from ArsTechnica

More from ETH Zurich via Nanowerk

Al Fin research oncologists and molecular biologists feel that Benenson's approach is more than a bit awkward and prone to breaking down. But he is working at a level of gene regulation which should prove relatively safe, as it moves closer to clinical research. And he is working at a level of complexity which should prove fertile for learning more about the molecular networks of cancer.

Expect some fascinating developments to come from this line of research.

Switching Off Cancer Using Nanoparticles

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Ribas said:

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

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

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

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

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

H/T Cuanas

Will This Metallomolecule Help to Extend Life?

Perhaps it will extend life. It can kill cancer, kill deadly resistant microbes, and may become a key part of the SENS anti-aging platform. Here is how:

The compound [Fe2L3]4+ is an iron triple helicate with three organic strands wrapped around two iron centres to give a helix which looks cylindrical in shape and neatly fits within the major groove of a DNA helix. It is about the same size as the parts of a protein that recognise and bind with particular sequences of DNA. The high positive charge of the compound enhances its ability to bind to DNA which is negatively charged.

When the iron-helicate binds to the major groove of DNA it coils the DNA so that it is no longer available to bind to anything else and is not able to drive biological or chemical processes. _PO

The interesting structure known as [Fe(2)L(3)](4+) was first researched as a treatment for cancer. But University of Warwick researchers have discovered that the metallomolecule is a particularly potent killer of bacteria -- even bacteria that are resistant to conventional antibiotics.

Initially the researchers focused on the application of this useful property for targeting the DNA of cancer cells as it could bind to, coil up and shut down the cancer cell's DNA either killing the cell or stopping it replicate. However the team quickly realised that it might also be a very clever way of targeting drug-resistant bacteria.

New research at the University of Warwick, led by Dr Adair Richards and Dr Albert Bolhuis, has now found that the [Fe2L3]4+ does indeed have a powerful effect on bacteria. When introduced to two test bacteria Bacillus subtilis and E. coli they found that it quickly bound to the bacteria's DNA and killed virtually every cell within two minutes of being introduced - though the concentration required for this is high. _PO

It will be important for the researchers to learn ways that the compound can be preferentially transported across bacterial membranes, to bacterial DNA. By reducing the necessary concentrations needed to kill the bacteria, and by making the construct preferentially attracted to pathological bacteria rather than to normal human cells, the safety and the efficacy of any possible future treatment using this compound will be enhanced.

The prevalence of antibiotic resistance has resulted in the need for new approaches to be developed to combat previously easily treatable infections. Here we investigated the potential of the synthetic metallomolecules [Fe(2)L(3)](4+) and [Cu(2)(L')(2)](2+) as antibacterial agents.... [Fe(2)L(3)](4+) binds in the major groove and causes DNA coiling... The work described here shows that ... [Fe(2)L(3)](4+) is bactericidal for Bacillus subtilis and Escherichia coli. We demonstrate that [Fe(2)L(3)](4+) binds bacterial DNA in vivo and, strikingly, that it kills B. subtilis cells very rapidly. _IntJnlAntimicrobialAgents

Cytocidal approaches are valuable medically to the extent they can be targeted and controlled -- with only limited damage to normal cells and tissues.

One of the main pillars of the SENS anti-aging approach is the elimination of superfluous and dangerous cells that have outlived their usefulness. The more precisely that one can target cytotoxic molecules, the more useful they will be for anti-aging therapies in addition to more conventional medical disciplines such as oncology and infectious disease.

Cross-posted at Al Fin

Turbocharging Antibody Response to Cancer etc

The human immune system is a powerful deterrent to a wide range of diseases, including cancer. But it takes time to build an immunity to new diseases. Researchers at Scripps Research Institute have devised a synthetic adaptor that can generate an almost instant immune response to the protein target of one's choice.

Most vaccines - like those for measles or smallpox - prompt the immune system to build a standing army of antibodies against a virus or bacterium by injecting a deactivated version of the bug into the body.

But it can take weeks or months to build up immunity, and you have to catch people before they get infected. What's more, the approach doesn't always work - cancer and HIV vaccines have proved elusive.

So instead, Carlos Barbas and colleagues at the Scripps Research Institute in La Jolla, California, have developed dumb-bell shaped "adaptor" molecules that bind mouse antibodies to proteins on the surface of disease-causing agents, redirecting the antibodies' killing focus. In an earlier experiment they attached these molecules to a single kind of antibody in the lab, and injected these "retrofitted" antibodies into the mouse to kill tumour cells.

Now they have demonstrated that these synthetic molecules can bind many kinds of antibodies to cancer cells inside mice and reduce the size of implanted human tumours.

Four weeks after the molecules were injected, the colon tumours had shrunk by up to 90 per cent, and melanomas by 78 per cent (Proceedings of the National Academy of Sciences, DOI: 10.1073/pnas.0900147106). _NS

Even if this new immune therapy does not completely eradicate a tumour, by shrinking its size it gives the patient's medical team more time to chance upon the magic bullet treatment for that particular patient. Each person is different, so it is natural that a person's response to disease and therapy will be unique.

Interferon Makes Dormant Cells Vulnerable

Dormancy is an important protection mechanism of stem cells. First, it protects their genetic material from genetic alterations, which happen primarily during cell division. In addition, dormancy helps them escape attacks of many cytotoxins, which act only on dividing cells. _MNT

Many cancer stem cells are likewise dormant, which can protect them from chemotherapy. Waking these cancer stem cells up before chemotherapy is one way to kill more of them, and increasing chances for a remission. Interferon seems to wake stem cells up from a dormant state, and force them to divide. This makes them vulnerable to mutation and to cytotoxins.

Patients suffering from a type of blood cancer called chronic myelogenous leukemia who are treated with a drug called Gleevec almost always relapse after drug treatment has ended. Several patients were given interferon-alpha prior to the Gleevec treatment. Surprisingly, these patients experienced long relapse-free phases without any medication. "We believe that the leukemia stem cells were awakened by the interferon administration and, thus, were sensitized to elimination by Gleevec," Andreas Trumpp explains. _MNT

The other side of the story is that interferon makes normal stem cells vulnerable to cytotoxic agents, so that blood forming stem cells in the bone marrow will be killed by some chemotherapeutic agents such as 5-FU, if interferon is given first. This can cause severe anemia and death.

This knowledge can lead one to speculate about the effects of viral infections and natural interferon on stem cells in other locations, such as the brain. The constant infectious assault experienced in the tropics, for example, may lead to chronic depletion of stem cells with all of the failure of normal regeneration that such depletion implies.

Each scientific discovery becomes the trigger for new exploration. The contemporary human mind cannot keep up with the multiple ongoing chain reactions of knowledge, but computers should be of some help.

Virus vs. Cancer: Reolysin Reovirus in Multiple Human Trials

Viruses are hardy pre-lifeforms, that have played a major role in the evolution of humans and other animals and plants. The articles featured in this posting deal with the reovirus labeled Reolysin, by Canadian company Oncolytics.

The novel anti-cancer therapy, REOLYSIN®, is a living virus, not a chemotherapy drug, that is toxic to cancer cells but not harmful to normal cells. This novel therapy, using a living virus, is the first of its kind available at CTRC.

...“This novel therapy has shown success because the reovirus replicates in and destroys the cancer cells within the patient’s body,” said Mita. “Cancer cells have several molecular and genetic abnormalities. In normal, healthy cells, the reovirus is unable to reproduce because of an enzyme named PKR. The enzyme is suppressed in cancer cells, and therefore the reovirus can replicate in the cancer cell and kill it.”

“REOLYSIN® typifies the true targeted therapy approach that seeks to use fundamental differences between cancer and normal cells as the basis for effective anti-cancer approaches and we are thus very excited about the this study,” said Francis Giles, MD, director of the CTRC Institute for Drug Development.

From article discussing human trials of Reolysin for metastatic sarcomas to the lung.

Another trial is ongoing in the UK:

The trial (REO 010) has two components. The first is an open-label, dose-escalating, non-randomized study of REOLYSIN(R) given intravenously with docetaxel every three weeks. A standard dosage of docetaxel will be delivered with escalating dosages of REOLYSIN(R) intravenously. A maximum of three cohorts will be enrolled in the REOLYSIN(R) dose escalation portion. The second component of the trial will immediately follow and will include the enrolment of a further 12 patients at the maximum dosage of REOLYSIN(R) in combination with a standard dosage of docetaxel.

Eligible patients include those who have been diagnosed with advanced or metastatic solid tumours such as bladder, prostate, lung or upper gastro-intestinal cancers that are refractory (have not responded) to standard therapy or for which no curative standard therapy exists. The primary objective of the trial is to determine the Maximum Tolerated Dose (MTD), Dose-Limiting Toxicity (DLT), recommended dose and dosing schedule and safety profile of REOLYSIN(R) when administered in combination with docetaxel. Secondary objectives include the evaluation of immune response to the drug combination, the body's response to the drug combination compared to chemotherapy alone and any evidence of anti-tumour activity. This is the third trial beginning in 2007 that is examining the role of REOLYSIN(R) in combination with standard chemotherapeutics.

Source

An animal model study using childhood sarcoma cell lines demonstrated significant activity of Reolysin against childhood sarcomas.

Particular viruses can be very useful for treating human disease, and eventually for augmenting normal human function and lifespan. That is because viruses have evolved to be excellent gene therapy vectors, and clever cell sneaks. Viruses can slip into cells and into cell nuclei, and have their way with the cell and its transcriptional apparatus--before the cell is even aware that anything has changed.

Viral therapies have the potential to be misused or misdirected, just like any other revolutionary approach to medicine and life extension. But it is important to understand that the tools that viruses bring to the table are significant, and are the result of billions of years of viral/cellular co-evolution.

Care for a Brand New Thymus?

Japanese scientists have built an artificial "lymph node" from thymus tissue, and transplanted it into immunodeficient mice.

The researchers, from RIKEN's Research Center for Allergy and Immunology in Yokohama, constructed their mouse aLNs by impregnating a two- to three-millimeter-diameter scaffold of the fibrous structural protein collagen with connective tissue extracted from the thymus of newborn mice and dendritic cells. Earlier work suggests that it is the connective tissue stromal cells which organize the structure of lymph nodes.

The aLNs were initially implanted into mice with a normal, healthy immune system, which had previously been injected with a harmless antigen compound to trigger an immune response. So the aLNs became populated with immune system T-cells and B-cells which specifically recognize and counter germs or cancer cells expressing the injected antigen.

These primed aLNs were then transplanted into two sets of mice--a group with a normal immune system which had never been exposed to the antigen, and a group in which the immune system did not function. When then exposed to the antigen both groups responded immediately by making appropriate protective antibodies--and the response to the antigen lasted for longer than four weeks, which means immune cells which retained 'memory' of the antigen had been generated.

Further investigation of the immunodeficient mice showed that T- and B-cells from the aLNs migrated to their spleens and bone marrows and were there generating large numbers of antigen-specific antibody-forming cells. The results also revealed some of the compounds involved in directing this migration process.

Source
This research has implications for the study of treatments for immune diseases, cancer, aging, and infectious disease such as AIDS. Thymosin is one of the several hormone levels that falls abruptly in the aging human. Growing an artificial thymus to boost thymosin levels appears within reach, if proven to be beneficial.

Also, here is a free collection of articles on Nanotechnology in Cancer.

And, here is more on an improved method for cervical cancer screening.

Better screening and better treatments. The two need to go hand in hand. Add better prevention to the mix and you are getting somewhere.

Biological Flavonoids--Don't Throw them Away Just Yet

A recent study from the Linus Pauling Institute at OSU Corvallis concludes that bioflavonoids have little if any use as antioxidants.

The study, published in Free Radical Biology and Medicine, found flavonoids are highly metabolized, which alters their chemical structure and diminishes their ability to function as an antioxidant. Although the compounds appear to have three to five times more antioxidant capacity than vitamins C or E, the body sees them as foreign compounds and modifies them for rapid excretion in the urine and bile

Source

The authors further stated that biological flavonoids may induce the body to excrete more carcinogens, and possibly reduce the risks of cancer and heart disease through other mechanisms than antioxidant activity.

Another study, from Denmark, purports to show that consumption of anti-oxidant supplements such as Vitamin C, Vitamin A, Vitamin E, and Beta Carotene--among others--are of no use in prolonging life and may actually increase morbidity and mortality.

Both of these studies have been used in an attempt to prove that the consumption of vitamins and phytonutrients are of limited if any benefit in the quest to prolong life and reduce risk of illness.

Unfortunately, the Danish study appears to confuse association with causation--a common error among researchers poorly trained in epistemology--and the Linus Pauling Institute study failed to follow the physiology of ingested flavonoids far enough.

It is abundantly clear that many researchers, in their eagerness to publish, fail to think their subject through clearly enough to present a coherent and valid conclusion to either the public, or to fellow scientists. This is more the fault of the competitive environment of modern science than a sign of intellectual or character deficits in the researchers. It is a publish or perish world for academics and researchers.

Quercetin, Resveratrol, Curcumin, Green Tea, Ginger, proanthocyanidins, and other plant-derived nutrients have demonstrated significant potential for reduction of morbidity of many types.

Many flavonoids have demonstrated clear anti-inflammatory effect in various biological models and syndromes. A serious researcher would look further for the source of the physiologic effects of flavonoids, rather than issuing a blanket statement of "no effect" with respect to the narrow issue of particular ways of measuring anti-oxidant activity in vivo. Much more was left undone and unsaid that is of far more importance, than what was demonstrated.

Particularly disappointing is the response of "science blogs" reporting on these and similar studies. Unfortunately, a false image of the underlying facts has been projected to the lay public, which may have unfortunate long term results for some.

Mitochondrial Paradigm for ... Aging and Cancer

In looking at aging, it is not enough to look at the nuclear genome. One must also look at the mitochondrial genome, and how the mitochondria interact with the nuclear genome.

Dr. Wallace looks at the ancient history of mitochondria as a free-living organism, and the subsequent symbiosis of mitochondria living inside eucharyotic cells. Then he looks at the mitochondrial genome and how it might affect a person's prospects for a long healthy life. 58 minutes.

Zeroing In on Genetic Mechanisms of Ageing

The genes are largely responsible for how we look, how intelligent we are, and how long we will live. Finding genes that help determine our lifespan is important in the quest to scientifically extend the human lifespan. Now, scientists have zeroed in on one likely gene candidate, p16INK4a, that when over-expressed leads to cellular senescence in pancreatic islet cells, brain, and blood stem cells.

Teams from the medical schools at the University of North Carolina at Chapel Hill, University of Michigan and Harvard University observed similar results in pancreatic islet cells and brain and blood stem cells.

The results show disparate cell types share a common aging mechanism and suggest that aging-related diseases such as diabetes result from a failure of cell growth, said Dr. Norman E. Sharpless, co-author on the three studies and an assistant professor of medicine and genetics at the UNC School of Medicine. "The studies indicate that certain stem cells lose their ability to divide and replace themselves with age as the expression of p16INK4a increases," said Sharpless, a member of the UNC Lineberger Comprehensive Cancer Center.

The trio of reports are published online Sept. 6 in the journal Nature. The three research teams are from the medical schools at UNC, the University of Michigan and Harvard University.

The UNC study focused on p16INK4a effects on the function of pancreatic islet cells. Islet cells are responsible for insulin production and secretion. Because p16INK4a stops cancer cells from dividing and demonstrates increased expression with age, the scientists suspected the gene played a similar role in aging. The researchers developed strains of mice that were either deficient in p16INK4a (the gene was deleted, or 'knocked out") or genetically altered to have an excess of the protein to a degree seen in aging.

According to Sharpless, islet proliferation persisted in p16INK4a -deficient animals as they aged, "almost as if they were younger animals." In mice with an excess of p16INK4a, "islet cells aged prematurely; they stopped dividing early."

"This suggests that if we could attenuate p16INK4a expression in some way in humans, it could lead to enhanced islet re-growth in adults and a possible new treatment for diabetes," Sharpless said.

Similar results were found in the other studies, which focused on brain stem cells and blood stem cells.

The Michigan researchers, led by Dr. Sean Morrison, examined the role played by p16INK4a in neural stem cells, progenitor cells that can form new neurons and other brain cells. The team showed that p16INK4a increases markedly in those cells with aging. Moreover, p16INK4a -deficient neural stem cells work better and don't age to the same extent that wild-type (normal) stem cells do, Sharpless said.

Dr. Janakiraman Krishnamurthy, lead author of the UNC study and a postdoctoral scientist in the Sharpless lab, was a co-author of the Michigan report. The Harvard team, led by Dr. David Scadden, studied the role of p16INK4a in hematopoietic stem cells, which proliferate continuously during the adult lifespan and produce massive amounts of new blood cells on an hourly basis. Their results suggest that p16INK4a is the molecular basis for an old-age "signal" previously observed in blood stem cells. The Harvard study also showed that blood stem cells from old mice lacking p16INK4a functioned better than old cells from wild-type mice, suggesting p16INK4a causes aging of these cells as well.

Sharpless cautions that any promise of a potential new aging treatment based on p16INK4a should include two important caveats. "First, even though old mice lacking p16INK4a show enhanced stem cell function, they do not live longer. This is because p16INK4a is an important cancer-suppressor gene, and mice lacking p16INK4a develop more cancers than old, normal mice," he said.

"Secondly, in all three studies, p16INK4a loss was associated with an improvement in some but not all of the consequences of aging. There are clearly things in addition to p16INK4a that contribute to aging. We don't yet know what they are."

Source.

Now it would be helpful to find a drug or genetic therapy that would block the anti-senescence effect of p16INK4a, but leave the tumour suppressor effect of the gene intact. I suspect that such a treatment would show significant pro-longevity effects.

There are many more pieces of this puzzle to find, but finding this particular piece will lead to the quicker finding of subsequent pieces.