Mastering Dynamic Cell Signaling

The following article was first published on Al Fin Longevity blog

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.

Keeping Abreast (or two) of Regenerative Medicine

Regenerative medicine is based upon thebody's ability to build itself -- and to often re-build itself after injury.  We are seeing breakthroughs in stem cell technologies virtually every week.  New technologies that allow physicians to use a patient's own cells to re-build a lost or damaged body part will avoid problems with immune rejection and ethical objections.  And if the touchstone for the explosion of regenerative medicine happens to be the human breast -- who can complain?

How to Build a New Breast

Cytori’s process for reconstructing or augmenting breasts relies on the recent discovery that human fat contains an amazing concentration of stem cells—cells that can be separated out using a centrifuge. That’s the science part. The artistry comes in when the surgeon makes tiny incisions for depositing the enriched fat cells, building a breast one dot-sized injection at a time like a 3-D pointillist. Here’s how it works.

Step 1 Liposuction

Breast reconstruction usually starts in the abdomen, using liposuction to harvest fat cells. Each liposuction syringe holds about 60 cc (2 fluid ounces) of fat cells and takes five minutes to fill. Repairing the divot caused by an average lumpectomy requires eight to 10 syringes to get about 360 cc of fat tissue. Half the fat is used to create the volume needed to fill the divot and half is processed to isolate stem and regenerative cells. A typical augmentation requires 800 cc (27 ounces) of liposuctioned fat: Volume varies, but in one study 160 cc of injected stem-cell-enriched tissue boosted breast circumference an average of 4 centimeters (1.6 cup sizes).

Step 2 Centrifugation

The liposuctioned fat is injected into the Celution System. ›› The fat cells are then “washed” with proprietary enzymes that break down the scaffolding that holds the fat cells together. ›› Next, a centrifuge separates the fat cells from the stem and regenerative cells, concentrating them into a pellet, which is then extracted. ›› The pellet of cells is added back to some of the liposuctioned fat cells, producing a liquid suspension enriched with stem and regenerative cells and ready for injection.

Step 3 Injection

Using a tool called the Celbrush, the surgeon repeatedly deposits the enriched cells in the breast, either at the site of a lumpectomy or throughout the breast for augmentation or repair of a mastectomy.

With reconstruction patients, the tip on the brush makes tiny cuts that perforate scarred areas, transforming the bed of damaged tissue into a biological mesh. The Celbrush releases 0.5 cc of cell-enriched tissue each time the surgeon moves its control wheel. The process typically takes a couple of hours, depending on the extent of treatment. The deposited tissue bonds quickly to the existing tissue. Within 48 hours, new capillaries and blood vessels entwine through the new cells, supplying oxygen and nutrients to the now-stable tissue. ›› The injection area isn’t painful afterward; patients go home the same day.

Source
More from Brian Wang

New RiPS Stem Cells May Become Therapeutic Breakthrough

Scientists have invented an efficient way to produce apparently safe alternatives to human embryonic stem cells without destroying embryos, a long-sought step toward bypassing the moral morass surrounding one of the most promising fields in medicine.

A team of researchers at the Harvard Stem Cell Institute in Boston published a series of experiments Thursday showing that synthetic biological signals can quickly reprogram ordinary skin cells into entities that appear virtually identical to embryonic stem cells. Moreover, the same strategy can then turn those cells into ones that could be used for transplants.

"This is going to be very exciting to the research community," said Derrick J. Rossi of the Children's Hospital Boston, who led the research published in the journal Cell Stem Cell. "We now have an experimental paradigm for generating patient-specific cells highly efficiently and safely and also taking those cells to clinically useful cell types."

Scientists hope stem cells will lead to cures for diabetes, Alzheimer's disease, spinal cord injuries, heart attacks and many other ailments because they can turn into almost any tissue in the body, potentially providing an invaluable source of cells to replace those damaged by disease or injury. But the cells can be obtained only by destroying days-old embryos. _WaPo

A new induced stem cell technique from Harvard scientists promises to snowball into a bona fide breakthrough in regenerative medicine. Using messenger RNA (mRNA), a Harvard team has developed a safe and efficient technique for transforming virtually any cell type into an induced pluripotent stem cell.

Rossi said it was a happy coincidence that using RNA instead of changing the DNA was as much as 100-fold more efficient. He said the effect was possibly because the process more closely reflects how cells themselves transform.

Rossi successfully differentiated his stem cells into muscle cells using RNA, a process that may offer promise in gene therapy and other treatments. His method does not alter the cell's underlying genome, though Rossi admits that he does not yet understand what it does to the cell's epigenome, which controls expression of genes.

Rossi said that his cells, which he's named RiPS, for "RNA induced Pluripotent Stem" cells, are more like embryonic stem cells than traditional iPS cells because they have not been genetically altered.

Melton said the Harvard Stem Cell Institute, which includes several hundred stem-cell researchers from across Harvard University and its affiliated hospitals, will now be making its standard iPS cells with Rossi's method. _TechnologyReview

See WaPo RiPS video

Genetics Magic: Two Examples of a Startling Future

Here are two fascinating examples of genetics magic:

Brain cells from skin cells

Skin cells called fibroblasts can be transformed into neurons quickly and efficiently with just a few genetic tweaks, according to new research. The surprisingly simple conversion, which doesn't require the cells to be returned to an embryonic state, suggests that differentiated adult cells are much more flexible than previously thought.

If the research, published in the journal Nature yesterday, can be repeated in human cells, it would provide an easier method for generating replacement neurons from individual patients. Brain cells derived from a skin graft would be genetically identical to the patient and therefore remove the risk of immune rejection--such an approach might one day be used to treat Parkinson's or other neurodegenerative diseases.

"It's almost scary to see how flexible these cell fates are," says Marius Wernig, a biologist at the Institute for Stem Cell Biology and Regenerative Medicine at Stanford, who led the research. "You just need a few factors, and within four to five days you see signs of neuronal properties in these cells." _TechnologyReview

Humans will soon be living longer, but in order for those longer lives to be meaningful, humans must have ways to keep their brains and other organs young and fully functional. Using common skin fibroblasts to provide replacement cells for aging brains would be the bare beginning steps to the regenerative society.



Diesel from bacteria

Jay Keasling, professor of chemical engineering and bioengineering at UC Berkeley and one of LS9's founders, and scientists at LS9 report engineering E. coli bacteria to synthesize and excrete the enzyme hemicellulase, which breaks down cellulose into sugars. The bacteria can then convert those sugars into a variety of chemicals--diesel fuel among them. The final products are excreted by the bacteria and then float to the top of the fermentation vat before being siphoned off.

Using these methods, it's possible to create a range of fuels from biomass, but LS9 is focusing on diesel rather than fuels similar to gasoline for the time being, says Stephen del Cardayre, the company's vice president of research and development. Diesel specifications are easier to meet and the market for diesel is growing by 2 to 4 percent a year, while that for gasoline is flat. Last May, LS9 partnered with Procter & Gamble to develop fuels as well as commodity chemicals. _TechnologyReview

Biomass can be grown in the oceans, in the deserts, on land, and in all ranges of climate. If a microbe can easily convert biomass to fuels on a large enough scale, you can say goodbye to fears of energy depletion.

The reprogramming of cellular genetic mechanisms allows humans to use living cells as molecular manufacturing plants, and as cell replication factories.   Programmed replacement brain cells can perform their normal functions plus secrete neuroprotective molecules to preserve their neighbors.  Re-programmed probiotics in the gut can provide a full range of nutrients and supplementary molecules to promote full body regeneration.  Programmed cells in the skin can use sunlight to synthesise a wide range of energy-providing molecules to power the body and brain.   Programmed biomass can turn itself into gasoline, diesel, jet fuel, etc. with a minimum of post-harvest processing.



When you look at all of the phantom fears held over our heads by the zombies in government, the UN, the media, and the rest of our fearful culture,  you need to understand that there are solutions to virtually every problem.  More importantly, you need to learn to distinguish problems that are fabricated to control your behaviour from problems that desperately require your attention to be solved.

Hopeful Stem Cell News Stories

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

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

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

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

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

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

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

Cross-posted at Al Fin Longevity

New One-Step Reprogramming to Pluripotent Stem Cells

Scientists at UCSD and Salk have discovered a quicker and safer way to turn mature human cells into pluripotent stem cells. The new method only requires a single factor, and avoids the risky and expensive use of viral vectors and complicated gene insertions.

"Working with neural stem cells, we discovered that a single factor can be used to re-program a human cell into a pluripotent state, one with the ability to differentiate into any type of cell in the body" said Muotri. Traditionally, a combination of four factors was used to create iPSCs, in a technology using viral vectors – viruses with the potential to affect the transcriptional profile of cells, sometimes inducing cell death or tumors.

...By creating iPSCs from human neural stem cells without the use of viruses, the scientists learned something new. While the genetic transcriptional profile of the new iPSCs was closer to that of embryonic stem cells than to human neural stem cells, the iPSCs still carried a transcriptional "signature" of the original neural cell.

"While most of the original genetic memory was erased when the cells were reprogrammed, some were retained," said Muotri. He added that, in the past, it wasn't known if this was caused by the use of viral vectors. "By using a footprint-free methodology, we have shown a safe way to generate human iPSCs for clinical purposes and basic research. We've also raised an interesting question about what, if any, effect the 'memory retention' of these cells might have."

...The study, led by UCSD Stem Cell Program researcher Alysson R. Muotri, assistant professor in the Departments of Pediatrics at UCSD and Rady Children's Hospital and UCSD's Department of Cellular and Molecular Medicine, will be published online in PLoS ONE on September 17. _SD_via_MachinesLikeUs

While it is currently necessary to study both adult and embryonic stem cells, eventually the safe use of induced pluripotent stem cells from the patient's own body will supplant most therapeutic uses of embryonic cells.

Fat Americans Declared National Resource

"We've identified a great natural resource," said Stanford surgery professor and co-author of the research, Michael Longaker, MD, who has called the readily available liposuction leftovers "liquid gold." _SD _ ImpactLab

Liposuction leftovers can be turned into induced pluripotent stem cells (iPS cells), which function remarkably like embryonic stem cells (ESCs).

Nestled within this unwanted latticework of fat cells and collagen are multipotent cells called adipose, or fat, stem cells. Unlike highly specialized skin-cell fibroblasts, these cells in the fat have a relatively wide portfolio of differentiation options—becoming fat, bone or muscle as needed. It's this pre-existing flexibility, the researchers believe, that gives these cell an edge over the skin cells. _SD

Now that we know how valuable liposuction leftovers can be, it may be time to re-think our approach to obesity and overeating. Stem cells are, after all, an important key to future medical advances. Anything that may restrict access to this vital resource needs to be vigorously opposed.

Stem Cell Renaissance? Behind the Hype . . . .

President Obama's long anticipated and much heralded signing of new federal guidelines for the financing of embryonic stem cell research will help US scientists learn more of the mysteries of embryonic cell differentiation and manipulation. But in reality, the effect of the new rules will be far less significant for the future of regenerative medicine than most gullible news consumers will ever know.

.....the president’s support of embryonic stem cell research comes at a time when many advances have been made with other sorts of stem cells. The Japanese biologist Shinya Yamanaka found in 2007 that adult cells could be reprogrammed to an embryonic state with surprising ease. This technology “may eventually eclipse the embryonic stem cell lines for therapeutic as well as diagnostics applications,” Dr. Kriegstein said. For researchers, reprogramming an adult cell can be much more convenient, and there have never been any restrictions on working with adult stem cells.

For therapy, far off as that is, treating patients with their own cells would avoid the problem of immune rejection.

Members of Congress and advocates for fighting diseases have long spoken of human embryonic stem cell research as if it were a sure avenue to quick cures for intractable afflictions. Scientists have not publicly objected to such high-flown hopes, which have helped fuel new sources of grant money like the $3 billion initiative in California for stem cell research.

In private, however, many researchers have projected much more modest goals for embryonic stem cells. Their chief interest is to derive embryonic stem cell lines from patients with specific diseases, and by tracking the cells in the test tube to develop basic knowledge about how the disease develops.

Despite an F.D.A.-approved safety test of embryonic stem cells in spinal cord injury that the Geron Corporation began in January, many scientists believe that putting stem-cell-derived tissues into patients lies a long way off. Embryonic stem cells have their drawbacks. They cause tumors, and the adult cells derived from them may be rejected by the patient’s immune system. Furthermore, whatever disease process caused the patients’ tissue cells to die is likely to kill introduced cells as well. All these problems may be solvable, but so far none have been solved.

Restrictions on embryonic stem cell research originated with Congress, which, each year since in 1996, has forbidden the use of federal financing for any experiment in which a human embryo is destroyed. This includes the derivation of human stem cell lines from surplus fertility clinic embryos, first achieved by Dr. James Thomson of the University of Wisconsin in 1998.

President Clinton contemplated but never implemented a policy that would have allowed N.I.H.-financed researchers to study human embryonic stem cells derived by others. Research was able to begin only in August 2001, when President Bush, seeking a different way around the Congressional restriction, said researchers could use any lines established before that date.

Critics said the distinction between the Clinton and Bush policies lacked moral significance, given that each was intended to get around the Congressional ban, based on a religious and moral argument. The proposed Clinton policy amounted to: “Stealing is wrong, but it’s O.K. to use stolen property if someone else stole it.” The Bush policy was: “Stealing is wrong, but it’s O.K. to use stolen property if it was stolen before Aug. 9, 2001.”

Mr. Obama has put the proposed Clinton policy into effect, but Congressional restrictions remain. Researchers are still forbidden to use federal financing to derive new human embryonic stem cell lines. They will, however, be allowed to do research on new stem cell lines grown in a privately financed lab. _NYT

More research on embryonic stem cells will help scientists understand the intricate mechanisms of cell development. The knowledge spinoffs from this research will stretch far beyond regenerative medicine (RM) to cancer treatments, life extension technologies other than RM, and a much deeper understanding of biological mechanisms in general.

But all of that would have occurred without that much celebrated penstroke yesterday. And it is undeniable that the flow of NIH funds to non-embryonic stem cell research has been a boon to technologies that are more immediately applicable to the everyday regenerative cell and tissue treatments of the future -- treatment using the patient's own cells.

Science under Obama is every bit as political as science under any other president -- and will probably only grow more political with time. Obama's promotion of carbon penalties (disguised as "cap and trade") are a politicised hyping of the pseudo science of catastrophic global warming from anthropogenic CO2. Obama's carbon hysteria-based political meddling in the energy industry is likely to make Americans far more miserable, leaving them with far less resources to deal with exigencies, than if he had done nothing at all.

So let's celebrate the abundant biological future that will eventually come to us via all the avenues of research being followed. And let us not fall for the hype surrounding the gilded age of Obamanation.

Everything Old is New Again

Old brains can start acting like young brains again, thanks to University of British Columbia researchers:

The research reveals that the loss of plasticity is due to the protein calpain actively blocking the protein cortactin, which is responsible for the sprouting of new connections. The researchers reduced calpain activity in animal models to unlock the sprouting potential of neurons and found that when calpain activity is reduced neural plasticity is enhanced.

“The maintenance of neuronal connections is an active process that requires constant repression of the formation of nerve sprouts by the protein calpain to avoid uncontrolled growth,” says Mingorance-Le Meur, who is also a member of the Brain Research Centre at UBC and VCH Research Institute. “But a consequence of this role is that calpain limits neural plasticity and the brain’s ability to repair itself. The next step is to find a way to enhance neural plasticity without interfering with the good connections that are already in place. The next step is to find a way to enhance neural plasticity without interfering with the good connections that are already in place.” _PO

Younger brains capable of learning rapidly could change a lot of things in the developed world, where populations are aging. Between 1% and 2% of populations in the developed world may be walking around with Alzheimer's, and the proportion will only grow unless we learn how to stop the inexorable senescence.

What about the rest of the body? How do we regenerate aging livers, kidneys, hearts, lungs, pancreases, lymphatics and blood vessels? We would probably start with stem cells. But we want our own stem cells -- stem cells that are compatible with our immune systems. Fortunately, science is unraveling the tangled knot of inducing pluripotent stem cells from adult cells:

A team led by Scripps Research Institute scientists has for the first time developed a technique for generating novel types of....human stem cells with characteristics similar to mouse embryonic stem cells, currently the predominant type of stem cells used for creating animal models of human diseases in research. The technique potentially provides scientists with new sources of stem cells to develop drugs and treatments for human diseases.

The study, which appears in the December 18 online version of Cell Stem Cell and the January 2009 print edition of the journal, provides proof of principle that alternative sources of stem cells can be created. _SD

The new technique apparently creates human induced pluripotent stem cells (hiPSCs) that are very close to hESCs in behaviour. This research suggests that before long, all of us will be able to bank our own hiPSCs as a type of "old age insurance" against the loss of function of virtually any tissue type.

The ability to grow entire new organs from hiPSCs has not been demonstrated, but it is only a matter of time and engineering. If hiPSCs behave like hESCs, all of the cell types to make any tissue or organ are there, potentially.

A lot more work is necessary before we can expect routine rejuvenation procedures from these breakthroughs. A lot of other breakthroughs will be necessary before the entire repertoire of rejuvenation techniques are available to significantly prolong the period of fulfilled and productive human lifespan.

Good news? Yes, but superficial good news. Underneath it all, humans are still generally stupid, unwise, ignorant, bigoted, easily led, fanatically violent creatures. The path to the next level does not involve superimposing all of the marvelous high tech accomplishments of western science and engineering onto the masses of humans. The transplant simply will not take, despite the best wishes of Kurzweil and friends.

More later.

Stem Cells from Testicles, Stem Cells from Microvessels

Scientists from Germany and the UK have modified adult stem cells grown from the testicles of humans into cells which appear to be almost identical to embryonic stem cells.

The new stem cells, known as human adult germline stem cells (GSCs), were grown by researchers in Germany and the U.K. by adding special growth factors to spermatogonial cells extracted from testes. Spermatogonial cells are stem cells in the adult testis that normally generate only one type of differentiated cell (sperm). But with the right growth factors, these spermatogonial cells can change to become pluripotent. They begin to produce proteins normally made by embryonic stem cells (ESCs) and acquire the ability to differentiate into many different cell types. _

This is an intriguing finding which will require confirmation and elaboration. If a man's testicles can produce stem cells easily modified to form germline stem cells (GSCs)--virtual ESCs--then most men with testicles would be able to grow his own replacement cells. The search is also on for a similar cell in women.

More recent good stem cell news: multipotent stem cells have been found on the walls of capillaries and microvessels.

The scientists, led by Bruno Péault, PhD, deputy director of the Stem Cell Research Center at Children's Hospital, identified cells known as pericytes that are multipotent, meaning they have broad developmental potential. Pericytes are found on the walls of small blood vessels such as capillaries and microvessels throughout the body and have the potential to be extracted and grown into many types of tissues, according to the study. _ScienceDaily

Those bits of stem cell news combined with improved methods of inducing pluripotent stem cells from adult cells, all paint a rosy picture of the future of stem cell therapies and regenerative medicine.

Shinya Yamanaka of Kyoto University reported a new method, described today in the journal Science, that uses a tiny ring structure called a plasmid to deliver genes into mouse cells and turn them into stem cells. The technique eliminates the need to use viruses, which can trigger cancer, to transform cells. _Bloomberg

The plasmid method of inducing pluripotent stem cells, when perfected for human cells, may well provide a safe way of generating pluripotent cells for those both with and without viable testicles.

The biotech revolution is just beginning. Combined with nanotech and advanced information science, the world of the very small is destined to grow very large.

Repair That Heart! Clever Muscle Cell Therapy Bypasses Transplant--Regenerative Medicine Comes of Age

Osaka University Hospital researchers have grown sheets of a patient's muscle cells (myoblasts) in the laboratory, then in the operating room applied these myoblast sheets to the patient's failing heart.

...the researchers first took about 10 grams of muscle from one of the patient’s thighs. Myoblast cells (a type of muscle stem cell) were then extracted from the muscle tissue, placed in a culture solution and grown into 50-micron-thick sheets measuring about 5 centimeters (2 inches) in diameter. Several layers of myoblast sheets were then applied to the surface of the impaired heart, where they helped strengthen the muscle and restore cardiac function.

Within months, the patient’s pulse rate and cardiac output (the amount of blood pumped from the heart with each contraction) returned to normal levels. The patient’s ventricular assist device was removed in September, and doctors say he will be able to lead a normal life after being released from the hospital at the end of this month.

Pink Tentacle

Clearly this procedure required extensive preparation and post-surgical rehabilitation. But consider what a heart transplant requires. Besides waiting for years for a donor, the surgery, the rehab, then a lifetime of anti-rejection drugs. No, clearly the myoblast approach is the winner--if it works.

Regenerative medicine is the process of using advanced cellular biology techniques to "refurbish" a failing organ. The heart is an obvious candidate for regenerative medical approaches. The kidneys, lungs, liver, and pancreas are others. Eventually, it will be possible to regrow any organ or tissue from adult stem cells (ASCs) using the appropriate scaffolding and growth factors, and knowing how to turn the proper genes on and off at the right times.

Kudos to the Osaka team.

Skin-Cell Stem-Cells Cure Sickle Cell Mice

An American team of scientists have cured mice of their sickle cell anemia using stem cells from skin cells--instead of cloned embryonic stem cells. This takes this no-clone stem cell approach yet one step closer to use on humans with genetic diseases and other conditions amenable to stem cell treatments.

A Japanese team made headlines worldwide a few days ago when it announced a way to turn adult skin cells, taken from a woman's face, into embryonic stem cells, the body's building blocks used during growth and repair, which offer a way to treat patients suffering a vast range of conditions with personalised replacement cells and tissue.

Now "direct reprogramming," which offers an alternative to the use of human eggs and cloning, has been used for the first time to cure a disease, marking the first "proof of principle" that this method has great promise in treating hereditary blood disorders, though the potential to rebuild a diseased or damaged body is much greater even than this.

Mice with the faulty gene responsible for human sickle-cell anaemia were treated successfully, so they made normal red blood cells instead of those of a sickle shape that clog blood vessels, causing severe pain, anaemia and, over time, a wide range of organ damage, even death.

More at Source

Much research needs to be done to ensure safety and efficacy of this technique for treating human diseases and/or trauma, but the early steps appear to lead in the right direction.

Adult Fibroblasts Reprogrammed to Become Embryonic Stem Cells?

This research appears to confirm earlier research published last year, that differentiated cells from adult mice can be induced to revert to the pluripotency of an embryonic stem cell.

Now, scientists at Whitehead Institute have demonstrated that embryonic stem cells can be created without eggs. By genetically manipulating mature skin cells taken from a mouse, the scientists have transformed these cells back into a pluripotent state, one that appears identical to an embryonic stem cell in every way. No eggs were used, and no embryos destroyed.

“These reprogrammed cells, by all criteria that we can apply, are indistinguishable from embryonic stem cells,” says Whitehead Member and MIT professor of biology Rudolf Jaenisch, senior author of the paper that will appear online June 6 in Nature.

What’s more, these reprogrammed skin cells can give rise to live mice, contributing to every kind of tissue type, and can even be transmitted via germ cells (sperm or eggs) to succeeding generations. “Germline transmission is the final and definitive proof that these cells can do anything a traditionally derived embryonic stem cell can do,” adds Jaenisch.

Two additional papers report similar findings. The first, by Shinya Yamanaka of Kyoto University, will be published in the same issue of Nature. The second, from Konrad Hochedlinger, formerly of the Jaenisch lab and now at Center for Regenerative Medicine at Massachusetts General Hospital and Harvard Stem Cell Institute, will appear in the inaugural issue of the journal Cell Stem Cells. Additionally, another paper in Nature from Kevin Eggan, also of the Harvard Stem Cell Institute and a former member of the Jaenisch lab, describes using mouse zygotes, rather than eggs, for somatic cell nuclear transfer.

Jaenisch cautions that “all these results are preliminary and proof of principle. It will be a while before we know what can and can’t be done in humans. Human embryonic stem cells remain the gold standard for pluripotent cells, and it is a necessity to continue studying embryonic stem cells through traditional means.”

In August 2006, a team of researchers at Kyoto University led by Yamanaka reported a landmark discovery that by activating four genes in a mouse skin cell, they could reprogram that cell into a pluripotent state resembling an embryonic stem cell. However, the resulting cells were limited when compared with real embryonic stem cells, and the Kyoto team was unable to generate live mice from these cells.

A team of researchers decided to replicate this experiment, while refining certain technical aspects.

Source

The approach taken by the researchers is intriguing, and so far appears to show that these reprogrammed mature fibroblasts are functionally and genetically indistinguishable from pluripotent ESCs.

Sperm Cells from Mesenchyme: Can Women Produce Sperm?

Human germ cells have been created from bone marrow stem cells for the first time. The researchers used bone marrow from male volunteers in this case, but could female donor stem cells work as well? Here is what the researchers did:

The research published today (Friday, April 13 2007), in the academic journal Reproduction: Gamete Biology, was carried out in Germany* by a team of scientists led by Professor Karim Nayernia, formerly of the University of Göttingen but now of the North-east England Stem Cell Institute (NESCI), based at the Centre for Life in Newcastle upon Tyne.

For the experiment, Prof Nayernia and his team took bone marrow from male volunteers and isolated the mesenchymal stem cells. These cells have previously been found to grow into other body tissues such as muscle.

They cultured these cells in the laboratory and coaxed them into becoming male reproductive cells, which are scientifically known as ‘germ cells’. Genetic markers showed the presence of partly-developed sperm cells called spermatagonial stem cells, which are an early phase of the male germ cell development. In most men, spermatagonial cells eventually develop into mature, functional sperm but this progression was not achieved in this experiment.

Earlier research led by Prof Nayernia using mice, published in Laboratory Investigations, also created spermatagonial cells from mouse bone marrow. The cells were transplanted into mouse testes and were observed to undergo early meiosis - cell division - the next stage to them becoming mature sperm cells, although they did not develop further.

Source

Stem cell researchers are becoming very adept at leading various types of stem cells down differentiational paths. Notice that these stem cells were taken from adult human males. They did not differentiate into functioning sperm, perhaps because they were not implanted into living testicles. Soon, however, it should be possible to produce sperm from stem cells in vitro--without the need for testicles.

If stem cells from the bone marrow of human females could eventually be coaxed into becoming functioning sperm, the dreams of creating a sustinable all-woman society could at last be within reach.

Fantastic Video of RNA Interference

If you liked The Inner Life of the Cell, you will be thrilled by RNAi, the video about RNA Interference a type of non-coding RNA. The narration in this video describes how RNAi participates in gene expression by blocking specific mRNAs from being translated.

Thanks again to Biosingularity Blog.

Contemplate what you learned from the above video when reading this newsrelease, describing a "masterswitch" for preserving adult stem cells in their primitive state.

Stem Cell Sources--The More, The Merrier!

It is becoming clearer that rich sources of multipotential stem cells exist in tissues other than a developing embryo. This should be good news to everyone, not just to the so-called "pro-lifers."

researchers from the Institute for Regenerative Medicine at Wake Forest University and Children's Hospital Boston found that amniotic cells in the laboratory can grow into all of the major types of cells, dividing at the rate of once every 36 hours. Researchers coaxed amniotic fluid stem cells to develop into brain cells and injected them into the skulls of mice with diseased brains. The stem cells replaced the diseased areas and appeared to create new connections with surrounding healthy neurons, the researchers reported. Researchers also coaxed amniotic fluid stem cells to become bone cells and implanted them in a mouse. The study found the stem cells calcified and turned into dense, healthy bone. The researchers also coaxed amniotic fluid stem cells to develop into muscle, fat, blood vessel and liver cells. Stem cells extracted from amniotic fluid can be isolated starting at 10 weeks' gestation from fluid taken during tests performed to identify birth defects, according to the study. The stem cells, even after more than two years in the laboratory, did not show signs of aging or of having the potential to grow into tumors, the study found. Amniotic stem cells can be frozen for later use, the Post reports.

Source.

Multipotent stem cells can be found in amniotic fluid, cord blood, the placenta, menstrual blood, testicular tissue, and probably many more tissues. That should be good news--

--but imagine my surprise to find that some people are making a political issue out of this.

Some politically involved people are acting as if these scientific discoveries somehow threaten the primary cause of radical feminist activists--abortion rights. But that sense of threat is clearly delusional, and evidence of paranoia.

Personally, I have no use for either extreme end of the political spectrum. Especially when they involve themselves in areas where they are completely incompetent.

Embryonic stem cell research holds incredible promise for the future. As the potential benefits and risks of stem cell therapies become better understood, it will probably be more important to make products of embryonic stem cells more widely available. Just as important is to understand all the potential sources of stem cells, and what they can be used for.

If adult stem cells can be used to create replacement tissues and organs, at least you know the cells will be MHC compatible if the recipient is also the donor. It may be discovered that adult stem cells will not work. Or a way to make embryonic stem cell products immunologically compatible with a wider range of recipients may be discovered. It's too early to say.

It is not too early to call political critics of non-embryonic stem cell research morons. As for critics of embryonic stem cell research, in the long run they are irrelevant.

Update: A reader has kindly emailed some specifics on the political reasons for certain persons publicly reacting against the amniotic fluid stem cell research. As I had thought, embryonic stem cells public proponents feel threatened by promising discoveries in non-embryonic stem cell research. This is unfortunate, but it is a good example of what happens when politics has undue influence on science.

It is extremely important that both embryonic stem cell research and non-embryonic stem cell research go forward. One are of research should not get all the funding, given all the potential problems that cannot be anticipated with one line or another.

Carbon Nanotubes Help Adult Stem Cells Replace Stroke Damaged Neurons

This is an excellent example of the convergence of nanotechnology and biotechnology. According to this Technology Review story, carbon nanotubes can be used as scaffolding to allow adult stem cells to differentiate to mature neurons, replacing neurons damaged by stroke.

Stem cells are a promising therapy for stroke and other brain injuries--they can sprout into healthy neurons and may be able to re-establish brain activity in brain-injured patients. While preliminary animal research shows promise, there's often a common hurdle: adult stem cells have a hard time growing in damaged areas and tend to migrate to healthier regions of the brain.

....Webster and his collaborators in South Korea found a possible anchor in carbon nanotubes: tiny, highly conductive carbon fibers that not only act as scaffolds, helping stem cells stay rooted to diseased areas, but also seem to play an active role in turning stem cells into neurons.

....Prior to this experiment, Webster had been experimenting with the properties of carbon nanotubes as possible neural implant material. Since nanotubes are highly conductive, they're an ideal template for transmitting electrical signals to neurons. In 2004, Webster was able to stimulate neurons to grow multiple nerve endings along carbon nanotubes. The study attracted the attention of South Korean stroke researchers, who proposed a collaboration: Why not use carbon nanotubes as a template for adult stem cells to grow into neurons? Taking it one step further, the team injected this nano-cocktail directly into the stroke-damaged brain regions of rats.

In order to determine how well the two therapies work together, the team compared the effects of injections of both stem cells and nanotubes with control groups injected with only adult stem cells or carbon nanotubes. After one and three weeks, researchers sacrificed the rats and examined the diseased areas of their brains. In rats who had received only adult stem cells, the cells tended to stray to healthier regions of the brain. But rats given both nanotubes and cells showed new neural growth in stroke-damaged brain regions in as little as a week.

Researchers aren't sure what makes carbon nanotubes such an effective template for stem cells--or how they help stem cells differentiate. But Webster says a likely answer to both questions is laminin, a glycoprotein in the brain's extracellular matrix that directs the generation of healthy nerve cells. The surface of carbon nanotubes resembles the elongated shape of laminin, and previous research has shown that nanotubes easily attract and adsorb laminin. Laminin, in turn, has a key amino acid sequence that attracts stem cells, stimulating them to turn into neurons. For these reasons, nanotubes may serve as pro-active delivery devices for stem cells.

More at Source.

Of course there are many other types of brain damage besides CVA. Brain tumours, brain abscesses, neurodegenerative and demyelinating diseases--all of these might profit from a reliable means of growing new neurons in-situ, from adult stem cells.

The entire field of growing biological tissue replacements should benefit from nano-technological scaffolding.

More Holistic Bio-ethanol, Pluripotent Adult Stem Cells, and more

Although I prefer bio-fuel alcohols be made from cellulose, cane, sorghum, or sugar beets, this report from Purdue Research Foundation suggests that maize (corn) may offer some advantages in terms of by-products.

A Purdue University team led by professor Li-fu Chen and research assistant Qin Xu, both from the Purdue food science department, discovered a new method to create ethanol from corn. The method also produces biodegradable byproducts that could be safely eaten.

"Our process, which we are calling the Chen-Xu Method, not only makes ethanol, but products that are fit for human consumption," Chen said. "This process also produces corn oil, corn fiber, gluten and zein, which is a protein that can be used in the manufacture of plastics so that the containers are good for the environment because they are biodegradable and easily decompose.

"The containers would actually be edible, although there probably wouldn't be much market for that."

Bio Processing Technology, based in West Lafayette, Ind., was formed to bring inventions from Chen and Xu to the marketplace. They have teamed with John Y.D. Tse, a management professor emeritus who is CEO of the startup company.

The Chen-Xu Method produces about 2.85 gallons of ethanol for every bushel of corn processed. That output is slightly higher than current methods, but the same process that creates the ethanol also creates other marketable products. Chen said the method also meets federal Clean Air Act standards, eliminating costs that other methods incur in meeting environmental regulations.

"One of the common methods of manufacturing ethanol, called dry milling, is often the cause of air pollutants by drying and storage of DDG, a byproduct of the process," Chen said. "Another method — wet milling — produces an odor because it requires the input of sulfur dioxide. The Chen-Xu Method eliminates both issues, and the only odor comes from the smell of the corn and yeast fermentation."

Using a machine originally designed to make plastics, the Chen-Xu Method grinds corn kernels and liquefies starch with high temperatures. The water input required by wet milling is reduced by 90 percent, Chen said. Wastewater output is cut by 95 percent, and electricity use is reduced by 47 percent.

"The total operating cost of a Chen-Xu Method ethanol plant should be much less than that of a wet-milling plant, and total equipment investment is less than half," Chen said. "And with proper planning and management, total equipment investment should be less than that of a dry-milling plant."

Source.

In the great stem cell race, it appears likely that Adult Stem Cells (ASCs) offer some advantages over Embryonic Stem Cells (ESCs). Of course, ASCs offer a level of biocompatibility that ESCs may not achieve, but now it seems that ASCs may offer another safety advantage--less risk of cancerous tumours. This newsrelease from University of Missouri-Columbia describes research that may expand the use of ASCs in the fairly near term.

"Embryonic stem (ES) cells are able to give rise to the remarkable diversity of cell types that constitute a whole organism such as a human," said Elmer Price, a scientist at the MU Dalton Cardiovascular Research Center and associate professor of biomedical sciences in the College of Veterinary Medicine. "However, this 'pluripotency,' or the ability of the cells to become anything, can also be a curse because ES cells can be misled by biochemical signals when they are transplanted into an adult during cell transplantation experiments. This often leads to the generation of unwanted cell types and, on occasion, tumor formation. Because of this, ES cell transplantation can raise serious safety issues. In this study, we developed adult stem cells from the blood of an mature animal that were able to be directed into specific cell types such as neurons and blood vessel cells, but they were not as pluripotent as ES cells. We have not observed any evidence of tumor formation."

Price extracted the adult stem cells from pigs' blood. These particular pig cells are unique because the pigs also contained a gene that makes their cells fluorescent. This allowed Price to track the cells as they developed into nerve or blood vessel cells or upon transplantation. The fluorescent pigs were created by MU animal scientist Randy Prather, who along with MU researcher Mike Foley, is a co-author of this paper.

In the study, Price was able to develop and sustain adult stem cell lines and then induce them to turn into specific cell types by exposing them to different chemical signals, depending on which type of cell he wanted to develop. For successful adult stem cell transplantation therapy, different diseases will require different cell types. Unlike embryonic stem cells, which are difficult to grow as pure cell populations and can develop into tumor-type tissue, Price's adult stem cells efficiently developed into specific cell types with no abnormal tissue.

"In theory, embryonic stem cells have the ability to become almost any cell type or organ," Price said. "Very complex chemical signals need to be in place with embryonic stem cells in order for them to develop into the appropriate type of cell. However, we have shown that if you can isolate adult stem cells, you can make them generate the appropriate type of cell with much more ease and specificity. One day, we may be able to isolate similar adult stem cells from a patient, manipulate the cells in a petri dish, and then re-introduce them back into that same patient as a therapy."

Source.

Is there any methane deep in the earth's mantle? That is a mystery that researchers from Lawrence Livermore and Argonne national laboratories, Carnegie Institution's Geophysical Laboratory, Harvard University, and Indiana University at South Bend are trying to solve.

For the methane experiments, researchers at the Geophysical Laboratory used Argonne's diamond anvil cell (DAC)—a small mechanical press that forces together the tips of two diamond anvils and creates extremely high pressures on a sample of a material held within a metal gasket. DACs allow researchers to measure material properties under static pressure and at varying pressures and temperatures over many hours. (See S&TR, December 2004, Putting the Squeeze on Materials.) Diamonds are used because they can withstand these ultrahigh pressures.

Also, their transparency permits diagnostic radiation, such as x rays and visible light, to pass unhampered through their crystalline structure.

Comparing Experimental Results with Calculations

To determine the chemical reactions that might occur at the pressures and temperatures of Earth's upper mantle, the researchers used the DAC to squeeze a microgram sample of iron oxide, calcite, and water to pressures up to 11 gigapascals at temperatures of more than 1300°C. Then they analyzed the results using Raman spectroscopy, synchrotron x-ray diffraction, and optical microscopy.

Raman spectroscopy measures the wavelength and intensity of scattered light from molecules as they vibrate about their bonds. These vibrations occur at certain frequencies. At normal pressures, electrons are tightly held within an atom's inner electron bands or shells. Squeezing a material under extreme pressures forces its atoms into a different orientation, which causes the delocalization of electrons and changes a material's properties and molecular structures.

By observing the frequency created when the electrons move or vibrate, scientists can tell how the elements are bonding to each other. Raman spectroscopy is highly sensitive to the stretching vibrations between carbon and hydrogen. The Raman spectra for the DAC samples showed hydrocarbon-rich regions.

The bond vibration between carbon and hydrogen becomes apparent in the spectra when the sample temperature reaches 500°C and is very strong by 600°C.

The researchers used synchrotron x-ray diffraction to determine the principal reaction products that occur as the DAC squeezes the samples. With synchrotron x-ray diffraction, a beam of x rays passes through the sample, and the resulting diffraction pattern is recorded on an x-ray film or detector. Changes in the pattern reveal how much of each element is involved in the chemical reaction at different temperatures and pressures. Diffraction results on the team's samples showed the presence of calcium oxide and magnetite—a chemically reduced form of iron oxide. When researchers examined the samples using optical microscopy, they again found changes indicating the presence of methane. Most notable were bubbles, which Raman measurements confirmed to be methane.

Source.

At a U Missouri-Columbia power plant, corn cobs will be used as a supplementary fuel with coal to determine if corn cobs might work as an economic fuel extender that is more environmentally friendly than burning pure coal.

Los Alamos and Sandia National Labs are both intensively involved in monitoring nuclear power plant activity. By learning to separate the short term radioactive from long term radioactive elements from nuclear waste, these labs intend to reduce the necessary space needed for long term nuclear waste storage. In addition, these two New Mexico National Labs are deeply involved in plans for producing hydrogen from nuclear energy, to help create the "hydrogen economy."

A lot of resources are being devoted to developing alternative energy sources to petroleum. At the same time, oil discovery methods are improving significantly--suggesting that peak oil is standing off well into the future.

Bio-medical research into stem cells, nanotech medicine, synthetic biology, and other radical new biomedical fields promises to improve the length and quality of the average person's life and health. The western world is poised on the brink of massive change for the better in several areas.

The bad news is that a lot of organisations and less organised groups of people do not want life to get better, unless it does so on their terms. These are political and religious ideologues who are enemies of individual liberties combined with wealth, because they do not like the choices that individuals make in spending their wealth. This blog will report--loosely--on the technological and scientific advances that are moving closer every day. But we will also be keeping an eye on the "killjoys and deadbeats" who want to spoil the party for the rest of us. These people are real and are very serious. We have to be just as serious in meeting the threat that they represent.

Multipotent Adult Stem Cells--More Sources

UPenn School of Medicine researchers have learned how to coax adult stem cells from hair follicles to grow into smoothe muscle cells, nerve cells, and melanocytes. While it has long been known that hair follicles contain adult stem cells, no one had succeeded in causing them to differentiate into different cell types until now.

“We are very excited about this new source of adult stem cells that has the potential for a variety of applications,” says senior author Xiaowei (George) Xu, MD, PhD, Assistant Professor of Pathology. “A number of reports have pointed to the fact that adult stem cells may be more flexible in what they become than previously thought, so we decided to look in the hair follicle bulge, a niche for these cells.” Xu and colleagues report their findings in the latest issue of the American Journal of Pathology.

Hair follicles are well known to be a source for adult stem cells. Using human embryonic stem cell culture conditions, the researchers isolated and grew a new type of multipotent adult stem cell from scalp tissue obtained from the National Institute of Health’s Cooperative Human Tissue Network.

The mutipotent stem cells grow as masses the investigators call hair spheres. After growing the “raw” cells from the hair spheres in different types of growth factors, the investigators were able to differentiate the stem cells into multiple lineages, including nerve cells, smooth muscle cells, and melanocytes (skin pigment cells).

The differentiated cells acquired lineage-specific markers and demonstrated appropriate functions in tissue culture, according to each cell type. For example, after 14 days, 20% to 40% of the cells in the melanocyte media took on a weblike shape typical of melanocytes. The new cells also expressed biomarkers typical of pigment cells and when placed in an artificial human skin construct, produced melanin and responded to chemical cues from normal epidermis skin cells.

After 14 days, about 10% of the stem cells in the neuronal cell line -- a type of cell not present in skin or hair -- grew dendrites, the long extensions typical of nerve cells and expressed neuronal proteins. The neurotransmitter glutamate was also present in the cells, but the neurotransmitter dopamine was not detected.

Thirdly, about 80% of the stem cells grown in the muscle media differentiated into smooth muscle cells. These new muscle cells also contracted when placed in a collagen matrix.

Source.

The selection of different growth media to bring about the differentiation of specific cell types is an art that is gradually developing into a science. As these tricks are tried on more adult stem cell types, it is possible that a fairly full palette of cell types might come available, from adult stem cells alone.

While multiple differentiation from embryonic stem cells has been studied and utilised by researchers for several years, the possibilities for multiple differentiation of adult stem cells has not been nearly as intensively looked into. This report indicates a slow trend that seems to be developing, to correct that ommission.

Stem Cells and Cancer: The Exquisite Dance

As many as 20% of cancers or more originate in stem cells. Our bodies are homes to hordes of stem cells, sometimes quiescent, sometimes regenerative, and sometimes proliferating out of control. The female breast is one organ that is amply supplied with stem cells.

"People have long suspected there should be a stem cell population in the human breast gland," said Sigurdsson who is part of the ESF-funded team led by Thorarinn Gudjonsson. A 'virgin' breast, before pregnancy, is very different to a fully functioning, milk-producing breast. With lactation, the breast becomes fully differentiated, and once this stage is over, it involutes. This cycle of proliferation, differentiation and apoptosis also happens in every menstrual cycle and in a more dramatic form during pregnancy. "This caught our attention, and has driven our research," Sigurdsson pointed out.

Breast cancer almost always occurs in the luminal epithelial compartment, which is also where milk is produced. Perhaps it is not surprising then, that stem cells reside in this compartment. In 2002, Thorarinn Gudjonsson, successfully isolated cells from the human breast with stem cell properties.

Gudjonsson immortalised these cells and grew them in three dimensional matrix that mimics the real, living tissue. Biologists have long relied on 2-dimensional cell cultures as the basic tool of their trade. But there is a big difference between a flat layer of cells and culturing cells in three-dimensions. The Icelandic researchers, realizing just how much a cells context matters, used the 3-D cell culture pioneered by Mina Bissell, at the Lawrence Berkeley National Laboratory in California. "We can build up a 3-D breast structure similar to what you have in vivo," says Gudjonsson.

"You can analyse cell-cell interactions and signaling pathways in these cells during morphogenesis and in cancer progression." The Icelandic researchers are now focusing their efforts on how endothelial cells convey signals to stem cells in normal breast formation and in cancer. In collaboration with another Icelandic research team, the Gudjonsson lab is now unraveling the role of tyrosine kinase receptors and their downstream signaling events. Source.

And so we see that stem cells are a two-edged sword in the breast. The same is true in other tissues. Stem cells are vital for regenerative functions, but must be held in check by tumour suppressor genes.

[A tumour suppressor gene,]PTEN functions to decide whether to progress further though the cell cycle or return to a quiescent (G0) state. Disrupting PTEN in stem cells results in more active cycling and a loss of the quiescent pool of stems cells that is necessary for long-term stem cell maintenance.

PTEN can be phosphorylated in response to other signals that modulate its function. The Li Lab's work demonstrated distinct populations of hematopoetic stem cells (HSCs) with phosphorylated and unphosphorylated forms of PTEN, suggesting that PTEN phosphorylation may be a 'sensor' that could help integrate external cues with the HSC quiescence/activation switch.

"Although the primary mutation occurs in stem cells, leading to short-term expansion of normal stem cells, this mutation alone is not enough to support unlimited expansion of either normal or cancer stem cells," said Dr. Li. "A secondary mutation is therefore required to empower the leukemia cells resulting from this mutation to undergo unlimited expansion. Exploring the nature of the secondary mutation, together with the primary mutation in PTEN, can help to understand the self-renewal ability of stem cells and perhaps will identify new molecules that can be targeted to provide effective leukemia treatment without adversely affecting normal stem cells." Source.

Sometimes the tumour suppressor genes are silenced, and if the tumour cells can maintain the silencing of the suppressor genes, the tumours are free to grow. Methylation is one means of gene silencing that tumours take advantage of.

Our cells become cancerous when the normal controls over cell growth and death go awry. This deregulation has traditionally been linked to DNA mutations of single genes or deletion of large sections of the chromosome. However more recently it has become clear that gene silencing in cancer can also occur, in the absence of changes to the DNA sequence: a phenomenon known as 'epigenetics'. DNA methylation is one of the main epigenetic processes.

In cancer, the DNA methylation pattern of many genes changes. However, until now, it was believed that only individual single genes were silenced by methylation. But this is not necessarily the case. "What we've found is that non-methylated genes that reside in a particular suburb near methylated genes are also silenced. Their physical proximity to the methylated genes affects their ability to function. It's a case of being in the wrong neighbourhood at the wrong time", says Assoc. Professor Clark.

The Garvan team developed a new method to scan the entire complement of the 30 000 plus genes - the entire genome - in the cancer tissue samples, which allowed widespread changes to be identified in specific parts of the genome.

They were amazed to find the extent of gene silencing. Assoc. Professor Clark adds: "What we want to do now is determine if these same regions are switched off in other types of cancers". Source.

Given that adult male testicles carry a sizable contingent of stem cells, it is perhaps surprising that testicular cancer is no more common than it is. There is considerable interest in testicular stem cells, and their possible potential in regenerative medicine. Projects are currently underway to learn how to extract and culture testicular stem cells in vitro. The following describes a project to culture specifically the spermatogonial stem cells, although more pluripotent cells are present.

"Our plan is to develop a culture system for spermatogonial stem cells" de Rooij told conference attendees. Although admitting the leap to humans is considerable, the colonised mouse testes are already providing useful insights.

"We'd like to know how to culture human spermatogenic stem cells to restore male fertility after cancer therapy," says Hannu Sariola, from the University of Helsinki in Finland who is also working towards a similar goal.

Bizarrely, a brain cell growth factor also has a powerful influence on spermatogonial stem cells. Glial cell derived neurotrophic factor (GDNF) is also involved in spermatogenesis: levels are high during the neonatal period and drop in adulthood. Indeed, mice that have been genetically manipulated to express high levels of GDNF in the testes produce huge clusters of spermatogonial stem cells. But the risk of cancer is boosted too, so it is not just about turning on the GDNF tap indiscriminately. It must be tightly regulated, Sariola pointed out.

The Dutch researchers are also hunting for the ideal conditions and nutrients that will coax spermatogonial stem cells into becoming sperm. So far, they have found that growth factors GDNF and fibroblast growth factor (FGF) seem to be necessary to enhance cell growth. The team's next move is to transplant monkey and human cells into the mouse testes system. Source.

Such are a few of the many molecular moves of the exquisite dance of the cell. It is not surprising that so many things sometimes go wrong. Rather, it is amazing that so many things go right for so long. But then, that is evolution's doing--we cannot take credit. The things that are coming, well, that is another matter.