Nerve cells actively repress alternative cell fates, researchers find

A neural cell maintains its identity by actively suppressing the expression of genes associated with non-neuronal cell types, including skin, heart, lung, cartilage and liver, according to a study by researchers at the Stanford University School of Medicine.

 It does so with a powerful . “When this protein is missing, neural cells get a little confused,” said Marius Wernig, MD, associate professor of pathology. “They become less efficient at transmitting nerve signals and begin to express genes associated with other cell fates.”

The study marks the first identification of a near-global repressor that works to block many cell fates but one. It also suggests the possibility of a network of as-yet-unidentified master regulators specific to each cell type in the body.

“The concept of an inverse master regulator, one that represses many different developmental programs rather than activating a single program, is a unique way to control neuronal cell identity, and a completely new paradigm as to how cells maintain their throughout an organism’s lifetime,” Wernig said.

Because the protein, Myt1l, has been found to be mutated in people with autism, schizophrenia and major depression, the discovered mode of action may provide new opportunities for therapeutic intervention for these conditions, the researchers said.

Wernig is the senior author of the study, which will be published online April 5 in Nature. Postdoctoral scholars Moritz Mall, PhD, and Michael Kareta, PhD, are the lead authors.


Myt1l is not the only protein known to repress certain cell fates. But most other known repressors specifically block only one type of developmental program, rather than many. For example, a well-known repressor called REST is known to block the neuronal pathway, but no others.

“Until now, researchers have focused only on identifying these types of single-lineage repressors,” said Wernig. “The concept of an ‘everything but’ repressor is entirely new.”

In 2010, Wernig showed that it is possible to convert skin into functional neurons over the course of three weeks by exposing them to a combination of just three proteins that are typically expressed in neurons. This “direct reprogramming” bypassed a step called induced pluripotency that many scientists had thought was necessary to transform one cell type into another.

 One of the proteins necessary to accomplish the transformation of skin to neurons was Myt1l. But until this study the researchers were unaware precisely how it functioned.

“Usually we think in terms about what regulatory programs need to be activated to direct a cell to a specific developmental state,” said Wernig. “So we were surprised when we took a closer look and saw that Myt1l was actually suppressing the expression of many genes.”

These genes, the researchers found, encoded proteins important for the development of lung, heart, liver, cartilage and other types of non-neuronal tissue. Furthermore, two of the proteins, Notch and Wnt, are known to actively block neurogenesis in the developing brain.

Blocking Myt1l expression in the brains of embryonic mice reduced the number of mature neurons that developed in the animals. Furthermore, knocking down Myt1l expression in mature neurons caused them to express lower-than-normal levels of neural-specific genes and to fire less readily in response to an electrical pulse.

‘A perfect team’

Wernig and his colleagues contrasted the effect of Myt1l with that of another protein called Ascl1, which is required to directly reprogram skin fibroblasts into neurons. Ascl1 is known to specifically induce the expression of neuronal genes in the fibroblasts.

“Together, these proteins work as a perfect team to funnel a developing cell, or a cell that is being reprogrammed, into the desired cell fate,” said Wernig. “It’s a beautiful scenario that both blocks the fibroblast program and promotes the neuronal program. My gut feeling would be that there are many more master repressors like Myt1l to be found for specific cell types, each of which would block all but one cell fate.”

Our Skin Has Smell Receptors That Help It to Heal Itself, Scientists Discover

Smell is one of the most ancient human faculties — it has also been the least understood by science until recently. Biologists first uncovered the inner workings of chemical sensors in our noses, otherwise known as olfactory receptors, in the early 1990s, a finding that lead to a Nobel Prize.

Our Skin Has Smell Receptors That Help It to Heal Itself, Researchers Discover

But the story doesn’t end there. Over the last decade, scientists have discovered that smell receptors are not only found in the nose, but also throughout the body — in the brain, colon, heart, liver, kidneys, spine, prostate and even sperm — and play a crucial role in a range of physiological functions. And now, a team of researchers at Ruhr University Bochum in Germany have confirmed even our skin is covered with these receptors.

“More than 15 of the olfactory receptors that exist in the nose are also found in human skin cells,” said lead researcher, Dr. Hanns Hatt. What’s more, exposing the skin receptors to specific odors triggers a cascade of reactions that prompt healing of injured tissue.

An Unconventional Way of Using Scent to Heal

The researchers in Germany are enthusiastic about our sense of smell — although, not via the nose, but the skin. Writes Bob Roeher in New Scientist:

“They found that Sandalore—a synthetic sandalwood oil used in aromatherapy, perfumes and skin care products—bound to an olfactory receptor in skin called OR2AT4. Rather than sending a message to the brain, as nose receptors do, the receptor triggered cells to divide and migrate, important processes in repairing damaged skin.

Cell proliferation increased by 32 per cent and cell migration by nearly half when keratinocytes [skin cells] in a test tube and in culture were mixed for five days with Sandalore.”

It may seem bizarre to have scent receptors beyond the nose, but Dr. Hatt and other researchers point out that odor receptors are some of the most evolutionarily ancient chemical sensors in the body, able to detect a profusion of compounds, not simply those floating in the air. It’s also not clear whether olfactory receptors in the nose were the first to develop in our evolutionary past.

“They’re called olfactory receptors because we found them in the nose first,” said Yehuda Ben-Shahar, a biologist at Washington University in St. Louis who published a paper in 2014 year on olfactory receptors in the human lung, which he found act as a safety switch against poisonous compounds by causing the airways to constrict when we inhale noxious substances. “It’s an open question,” he said, “as to which evolved first.” [source]

The receptors operate as a lock-and-key system, where an odor molecule acts like a key to the receptors lock. Only specific molecules will plug into specific receptors. When the right molecule “clicks” with the matching receptor, it activates a complex set of biochemical reactions.

“If you think of olfactory receptors as specialized chemical detectors, instead of as receptors in your nose that detect smell, then it makes a lot of sense for them to be in other places,” notes Jennifer Pluznick, an assistant professor of physiology at Johns Hopkins University who discovered in 2009 that smell receptors in the kidneys of mice help regulate metabolic function and control blood pressure.

This isn’t the first time science has discovered smell receptors in a strange place. In 2003, Dr. Hatt and his colleagues found that olfactory receptors within the testes function like a biochemical guidance system, which allows the sperm to locate an unfertilized egg. And in 2009, the team also reported that subjecting olfactory receptors in the human prostate to beta-ionone, a scent compound found in violets and roses, slowed the spread of prostate cancer cells by way of turning off misbehaving genes.

“I’ve been arguing for the importance of these receptors for years,” said Dr. Hatt, who calls himself an ambassador of smell, and whose favorite aromas are basil, thyme and rosemary. “It was a hard fight.” [source]

Grace Pavlath, a biologist at Emory University, is also intrigued by unusually placed olfactory receptors. While studying the receptors in skeletal muscles, she discovered that by soaking them in Lyral — a synthetic fragrance similar to lily of the valley — muscle tissue regeneration was increased. When she blocked the receptors, muscular regeneration was inhibited, leading her to believe that smell receptors are an integral part of the biochemical signaling system, which prompts stem cells to morph into muscle cells and heal injured tissue.

These findings hold promise for the development of pharmaceuticals and cosmetics, such as a smell-based drug that helps to regenerate muscle tissue after an injury, or a topical cream that would accelerate wound healing. The researchers are hopeful that new and innovative ways to utilize olfactory receptors is just around the corner.

Your Car Door Windows Do Not Shield Your Skin, Eyes From UV Rays

Prolonged exposure to the sun’s ultraviolet A (UV-A) rays has long been associated with increased risk for cataracts and skin cancer.

For many Americans who drive each day, their car’s front windshield protects them from the harmful rays. Findings of a new study, however, revealed that car door windows do not offer the same protection from the sun.

In a new research published in JAMA Ophthalmology on May 12, Brian Boxer Wachler, from the Boxer Wachler Vision Institute, analyzed the UV protection provided by glass in 29 cars that were produced between 1990 and 2014.

The researcher measured the levels of ambient UV-A radiation behind the cars’ front windshield and the side window and found that the windshield windows tend to provide good protection blocking 96 percent of UV-A rays on average. The protection, however, was lower at 71 percent and inconsistent for the cars’ side windows.

The research likewise revealed that only 14 percent of the cars have side windows that provide high level of UV-A protection, which could be to blamed in part for the increased prevalence of skin cancer on the left side of people’s faces and left-eye cataracts.

Based on his findings, Wachler said that automakers may want to consider boosting the amount of UV-A protection in the side windows of vehicles.

“Auto glass with UV-A protection would be expected to reduce the risks of disorders related to sun damage,” Wachler wrote in his study.

Jayne Weiss, from the Louisiana State University Eye Center of Excellence, explained that windshields provide more protection than car door windows because they are made of laminated glass designed to prevent shattering. The car door windows, on the other hand, are only tempered glass.

“Don’t assume because you are in an automobile and the window is closed that you’re protected from UV light,” Weiss said.

Although UV-B rays can be blocked by glass, UV-A is a longer wavelength of light that can go deeper into the skin and this can cause premature aging and even skin cancer.

Experts recommend using sunglasses that block both UV-B and UV-A lights as well as using long sleeve clothing and broad spectrum sunscreen particularly during long drives on sunny days. Drivers with older cars or those whose cars don’t have built-in protection can also buy special window tint products that provide shield against UV rays.

– See more at:

Scientists grow skin that replicates function of tissue for first time

Skin grown with follicles, glands and nerves could transform burns treatment and offer alternative to animal testing

Scientists seeking to replicate human skin, pictured, have grown functional elements for the first time.
Scientists seeking to replicate human skin, pictured, have grown functional elements for the first time.

Bioengineered skin complete with functioning hair follicles, glands and nerves has been grown using a new technique that could transform burns treatment and end cosmetics testing on animals.

Working with mice, scientists in Japan created the skin by first producing three-dimensional clumps of cells that resembled embryos in the womb.

They then implanted the so-called “embryoid bodies” into immune-deficient mice, where the cells developed further. Next, the maturing cells were grafted on to the bodies of other mice to complete their transformation into skin.

The end result was functional “integumentary tissue”, the deeply layered tissue that allows the skin to work as the body’s largest organ.

“With this new technique, we have successfully grown skin that replicates the function of normal tissue.

“We are coming ever closer to the dream of being able to recreate actual organs in the lab for transplantation, and also believe that tissue grown through this method could be used as an alternative to animal testing of chemicals.”

At the start of the study, cells taken from the gums of mice were turned into induced pluripotent stem cells by exposing them to a cocktail of chemicals that turned back their developmental clock. These were then coaxed to develop into EBs in the laboratory.

Previous attempts at growing skin from stem cells have only got as far as producing implantable sheets of epithelial cells, which formed the outermost skin layer but lacked functional elements such as oil-secreting sebaceous and sweat glands.

The skin produced by Dr Tsuji’s team made normal connections with surrounding nerve and muscle tissue and sprouted hair.

The research, reported in the journal Science Advances, brings effective regenerative treatments for patients with severe burns and skin diseases a significant step closer.

It could also provide an alternative to testing cosmetics and household products, such as detergents, on animals.

Animal cosmetics testing is illegal in the UK and other EU countries but continues in other parts of the world.

Measuring Blood Sugar With Light.

Technology designed in Germany may help people with Type 1 and Type 2 diabetes; described in Review of Scientific Instruments

WASHINGTON D.C. October 25, 2013 — One of the keys to healthful living with Type 1 and Type 2 diabetes is monitoring blood glucose (sugar) levels to ensure they remain at stable levels. People can easily and reliably do this at home using electronic devices that read sugar levels in a tiny drop of blood.

Now a team of German researchers has devised a novel, non-invasive way to make monitoring easier. Using infrared laser light applied on top of the skin, they measure sugar levels in the fluid in and under skin cells to read blood sugar levels. They describe their method in the current edition of Review of Scientific Instruments, which is produced by AIP Publishing.

“This opens the fantastic possibility that diabetes patients might be able to measure their glucose level without pricking and without test strips,” said lead researcher, Werner Mäntele, Ph.D. of Frankfurt’s Institut für Biophysik, Johann Wolfgang Goethe-Universität.

“Our goal is to devise an easier, more reliable and in the long-run, cheaper way to monitor blood glucose,” he added.

The “Sweet Melody” of Glucose

Their new optical approach uses photoacoustic spectroscopy (PAS) to measure glucose by its mid-infrared absorption of light. A painless pulse of laser light applied externally to the skin is absorbed by glucose molecules and creates a measurable sound signature that Dr. Mäntele’s team refers to as “the sweet melody of glucose.” This signal enables researchers to detect glucose in skin fluids in seconds.

The data showing the skin cell glucose levels at one-hundredth of a millimeter beneath the skin is related to blood glucose levels, Mäntele said, but previous attempts to use PAS in this manner have been hampered by distortion related to changes of air pressure, temperature and humidity caused by the contact with living skin.

To overcome these constraints, the team devised a design innovation of an open, windowless cell architecture. While it is still experimental and would have to be tested and approved by regulatory agencies before becoming commercially available, the team continues to refine it.

A Possible Cure for Baldness, in 3D.

Set the ball rolling. Human skin cells grown on a flat culture remain dispersed and unable to induce the formation of hair follicles (left). But in a 3D culture, the cells form spheres that can coax new hair follicle growth (right).

Christiano lab, Columbia University

Set the ball rolling. Human skin cells grown on a flat culture remain dispersed and unable to induce the formation of hair follicles (left). But in a 3D culture, the cells form spheres that can coax new hair follicle growth (right).

Scientists have successfully grown new hair follicles from the skin cells of balding men. While the research team hasn’t yet shown whether the structures, which produce strands of hair on our bodies, are fully functional and usable for transplants onto a scalp, experts say the discovery is a significant step toward finding new treatments for hair loss.

“Their work is very elegant and extremely rigorous,” says Radhika Atit, a skin biologist at Case Western Reserve University in Cleveland, Ohio, who was not involved in the new study. “This is a big technical advance.”

Balding occurs when hair follicles stop producing new strands of hair in any area of the body. Now, taking drugs that prevent or slow the hair loss or transplanting hair follicles from one area of the body to another are the only viable treatments. Producing new hair follicles in the lab has not been an option—at least for human patients. In mice, researchers have shown that if they isolate dermal papilla cells, which surround hair follicles in the skin, grow them in petri dishes to produce new cells, and then put the cells back in the mouse, new hair follicles will develop. But when dermal papilla cells from humans are put into dishes in the lab, they lose their ability to induce the formation of new follicles.

Angela Christiano, a skin researcher at Columbia University who has discovered genes related to hair loss, recently brainstormed potential solutions to the problem with her colleagues. They noticed that while the dermal papilla cells from mice naturally formed large clumps in culture, the human cells didn’t. “We began thinking that maybe if we could get the human cells to aggregate like the mouse cells, that might be a step toward getting them to form new follicles,” Christiano says.

Her team decided to try a cell-growing approach, called 3D cultures, that’s been successful for other types of cells that need to form complex structures as they grow. The researchers collected dermal papilla cells from seven volunteers who had been diagnosed with male-pattern baldness. Rather than stick the isolated cells on a flat culture dish, they mixed the cells with liquid, then let the mixture hang in tiny droplets from a plastic lid, like condensation on the roof of a container. Because the cells inside the droplets are free-floating, the technique allows them to contact each other in every direction, as they would in the human body, rather than only touch side to side as they do in a flat dish. In the droplets, the cells behaved differently; as they divided to form new cells, they clumped into what the researchers call “spheroids”—balls of about 3000 cells.

To test whether the new spheroids were a better mimic for functional dermal papilla cells than those that had been grown in typical dishes, Christiano and her team determined what genes were turned on and off in different sets of dermal papilla cells. In cells grown on flat culture dishes, the expression of thousands of genes didn’t match up with their normal patterns, explaining why the cells from those dishes had been unable to generate new hair follicles. But in the 3D cultures, 22% of those genes had been restored to their correct on or off state.

The researchers then took 10 to 15 of the spheroids that had formed from each donor and sandwiched them between two layers of human skin that were grafted onto mice. Six weeks later,spheroids from five of the seven donors had coaxed the skin cells around them to start rearranging, forming the telltale shape of a hair follicle, the team reports online today in the Proceedings of the National Academy of Sciences. In two cases, hairs were even seen beginning to extend from the follicles, though the researchers didn’t continue the initial experiment for long enough to test whether the hairs were fully normal in terms of their ability to regrow.

Using one’s own cells to generate new follicles is useful because hair color and thickness will match perfectly with the rest of someone’s head of hair, Christiano notes. And with the new tissue culture technique, clinicians would be able to take just a few dermal papilla cells from a balding patient and expand the number of hair follicles available for transplant, rather than only be able to move follicles around. “Using this technique could change the number of people who would be eligible for hair transplants,” Christiano says.

The success of the approach is exciting, but the real breakthrough for other researchers in the field is the new data on gene expression in dermal papilla cells, says George Cotsarelis, a dermatologist at the University of Pennsylvania. The full readout of what genes are on and off in dermal papilla cells has never been collected before, so researchers now have a new list of thousands of genes to study further that may play key roles in hair follicle development. “It could have implications for not just hair, but treating wounds and scarring,” he says.

The spheroids capable of producing hair follicles could also be used as a new way to test drugs for their ability to restore follicle function, Atit says. “This is a better model system to use for drug testing than a two-dimensional plate.”

Lab-Made Egg and Sperm Precursors Raise Prospect for Infertility Treatment.

A technical tour de force, which involved creating primordial germ cells from mouse skin cells, is prompting scientists to consider attempting this experiment with human cells

Since last October, molecular biologist Katsuhiko Hayashi has received around a dozen e-mails from couples, most of them middle-aged, who are desperate for one thing: a baby. One menopausal woman from England offered to come to his laboratory at Kyoto University in Japan in the hope that he could help her to conceive a child. “That is my only wish,” she wrote.


The requests started trickling in after Hayashi published the results of an experiment that he had assumed would be of interest mostly to developmental biologists. Starting with the skin cells of mice in vitro, he created primordial germ cells (PGCs), which can develop into both sperm and eggs. To prove that these laboratory-grown versions were truly similar to naturally occurring PGCs, he used them to create eggs, then used those eggs to create live mice. He calls the live births a mere ‘side effect’ of the research, but that bench experiment became much more, because it raised the prospect of creating fertilizable eggs from the skin cells of infertile women. And it also suggested that men’s skin cells could be used to create eggs, and that sperm could be generated from women’s cells. (Indeed, after the research was published, the editor of a gay and lesbian magazine e-mailed Hayashi for more information.)

Despite the innovative nature of the research, the public attention surprised Hayashi and his senior professor, Mitinori Saitou. They have spent more than a decade piecing together the subtle details of mammalian gamete production and then recreating that process in vitro — all for the sake of science, not medicine. Their method now allows researchers to create unlimited PGCs, which were previously difficult to obtain, and this regular supply of treasured cells has helped to drive the study of mammalian reproduction. But as they push forward with the scientifically challenging transition from mice to monkeys and humans, they are setting the course for the future of infertility treatments — and perhaps even bolder experiments in reproduction. Scientists and the public are just starting to grapple with the associated ethical issues.

“It goes without saying that [they] really transformed the field in the mouse,” says Amander Clark, a fertility expert at the University of California, Los Angeles. “Now, to avoid derailing the technology before it’s had a chance to demonstrate its usefulness, we have to have conversations about the ethics of making gametes this way.”

Back to the beginning
In the mouse, germ cells emerge just after the first week of embryonic development, as a group of around 40 PGCs. This little cluster goes on to form the tens of thousands of eggs that female mice have at birth, and the millions of sperm cells that males produce every day, and it will pass on the mouse’s entire genetic heritage. Saitou wanted to understand what signals direct these cells throughout their development.

Over the past decade, he has laboriously identified several genes — including Stella,Blimp1 and Prdm14 — that, when expressed in certain combinations and at certain times, play a crucial part in PGC development. Using these genes as markers, he was able to select PGCs from among other cells and study what happens to them. In 2009, from experiments at the RIKEN Center for Developmental Biology in Kobe, Japan, he found that when culture conditions are right, adding a single ingredient — bone morphogenetic protein 4 (Bmp4) — with precise timing is enough to convert embryonic cells to PGCs. To test this principle, he added high concentrations of Bmp4 to embryonic cells. Almost all of them turned into PGCs. He and other scientists had expected the process to be more complicated.

Saitou’s approach — meticulously following the natural process — was in stark contrast to work that others were doing, says Jacob Hanna, a stem-cell expert at the Weizmann Institute of Science in Rehovot, Israel. Many scientists try to create specific cell types in vitro by bombarding stem cells with signalling molecules and then picking through the resulting mixture of mature cells for the ones they want. But it is never clear by what process these cells are formed or how similar they are to the natural versions. Saitou’s efforts to find out precisely what is needed to make germ cells, to get rid of superfluous signals and to note the exact timing of various molecules at work, impressed his colleagues. “There’s a really beautiful hidden message in this work — that differentiation of cells [in vitro] is really not easy,” says Hanna. Harry Moore, a stem-cell biologist at the University of Sheffield, UK, regards the careful recapitulation of germ-cell development as “a triumph”.

Until 2009, Saitou’s starting point had been cells taken from a live mouse epiblast — a cup-like collection of cells lining one end of the embryo that forms at the end of the first week of development, just before the PGCs emerge. But to truly master the process, Saitou wanted to start with readily available, cultured cells.

That was a project for Hayashi, who in 2009 had returned to Japan from the University of Cambridge, UK, where, like Saitou before him, he had completed a four-year stint in the laboratory of a pioneer in the field, Azim Surani. Surani speaks highly of the two scientists, saying that they “complement each other in temperament and in their style and approach to solving problems”. Saitou is “systematic” and “single-minded about setting and accomplishing his objectives”, whereas Hayashi “works more intuitively, and takes a broader view of the subject and has outwardly a more relaxed approach”, he says. “Together they form a very strong team indeed.”

Hayashi joined Saitou at Kyoto University, which he quickly found was different from Cambridge. There was much less time spent on theoretical discussions than Hayashi was used to; instead, one jumped into experiments. “In Japan we just do it. Sometimes that can be very inefficient, but sometimes it makes a huge success,” he says.

Hayashi tried to use epiblast cells — Saitou’s starting point — but instead of using extracted cells as Saitou did, he tried to culture them as a stable cell line that could produce PGCs. That did not work. Hayashi then drew on other research showing that one key regulatory molecule (activin A) and a growth factor (basic fibroblast growth factor) could convert cultured early embryonic stem cells into cells akin to epiblasts. That sparked the idea of using these two factors to induce embryonic stem cells to differentiate into epiblasts, and then to apply Saitou’s previous formula to push these cells to become PGCs. The approach was successful.

To prove that these artificial PGCs were faithful copies, however, they had to be shown to develop into viable sperm and eggs. The process by which this happens is complicated and ill understood, so the team left the job to nature — Hayashi inserted the PGCs into the testes of mice that were incapable of producing their own sperm, and waited to see whether the cells would develop. Saitou thought that it would work, but fretted. “It seemed like a 50/50 chance,” he says. “We were excited and worried at the same time.” But, on the third or fourth mouse, they found testes with thick, dark seminiferous tubules, stuffed with sperm. “It happened so properly. I knew they would generate pups,” says Hayashi. The team injected these sperm into eggs and inserted the embryos into female mice. The result was fertile males and females.

They repeated the experiment with induced pluripotent stem (iPS) cells — mature cells that have been reprogramed to an embryo-like state. Again, the sperm were used to produce pups, proving that they were functional — a rare accomplishment in the field of stem-cell differentiation, where scientists often argue over whether the cells that they create are truly what they seem to be. “This is one of the few examples in the entire field of pluripotent-stem-cell research where a fully functional cell type has been unequivocally generated starting from a pluripotent stem cell in a dish,” says Clark.

They expected eggs to be more complex, but last year, Hayashi made PGCs in vitrowith cells from a mouse with normal coloring and then transferred them into the ovaries of an albino mouse. The resulting eggs were fertilized in vitro and implanted into a surrogate. “I knew it had worked,” he says, when he saw the pups’ dark eyes pressing through their translucent eyelids.

Germ-cell bounty
Other researchers have been able to replicate the process to generate laboratory-grown PGCs (although none contacted by Nature had used them to produce liveanimals). Artificial PGCs are of particular use to scientists who study epigenetics: the biochemical modifications to DNA that determine which genes are expressed. These modifications — most often the addition of methyl groups to individual DNA bases — in some instances carry a sort of historical record of what an organism has experienced (for example, exposure to foreign chemicals in the womb). In a similar way to how they work in other cells, epigenetic markers push PGCs to their fate during embryonic development, but PGCs are unique because when they develop into sperm and eggs, the epigenetic markers are erased. This allows the cells to create a new zygote that is capable of forming all cell types.

Faults in subtle epigenetic changes are expected to contribute to infertility and the emergence of disorders such as testicular cancer. Already, Surani’s and Hanna’s groups have used the artificial PGCs to investigate the role of individual enzymes in epigenetic regulation, which may one day show how the epigenetic networks are involved in disease.

Indeed, the in vitro-generated PGCs offer millions of cells for scientists to study, instead of the 40 or so that can be obtained by dissecting early embryos, says Hanna. “This is a big deal because here we have these rare cells — PGCs — that are undergoing dramatic genome-wide epigenetic changes that we barely understand,” he says. “The in vitro model has provided unprecedented accessibility to scientists,” agrees Clark.

Clinical relevance
But Hayashi and Saitou have little to offer to the infertile couples begging for their help. Before this protocol can be used in the clinic, there are large wrinkles to be ironed out.

Saitou and Hayashi have found that although the offspring generated by their technique usually seem to be healthy and fertile, the PGCs that these offspring generate in turn are not completely ‘normal’. The second-generation PGCs often produce eggs that are fragile, misshapen and sometimes dislodged from the complex of cells that supports them. When fertilized, the eggs often divide into cells with three sets of chromosomes rather than the normal two, and the rate at which the artificial PGCs successfully produce offspring is only one-third of the rate for normal in vitrofertilization (IVF). Yi Zhang, who studies epigenetics at Harvard Medical School in Boston, Massachusetts, and who has been using Saitou’s method, has also found thatin vitro PGCs do not erase their previous epigenetic programming as well as naturally occurring PGCs. “We have to be aware that these are PGC-like cells and not PGCs,” he says.

In addition, two major technical challenges remain. The first is working out how to make the PGCs convert to mature sperm and eggs without transplanting them back into testes or ovaries; Hayashi is trying to decipher the signals that ovaries and testes give to the PGCs that tell them to become eggs or sperm, which he could then add to artificial PGCs in culture to lead them through these stages.

But the most formidable challenge will be repeating the mouse PGC work in humans. The group has already started tweaking human iPS cells using the same genes that Saitou pinpointed as being important in mouse germ-cell development, but both Saitou and Hayashi know that human signalling networks are different from those in mice. Moreover, whereas Saitou had ‘countless’ numbers of live mouse embryos to dissect, the team has no access to human embryos. Instead, the researchers receive 20 monkey embryos per week from a nearby primate facility, under a grant of ¥1.2 billion (US$12 million) over five years. If all goes well, Hayashi says, they could repeat the mouse work in monkeys within 5–10 years; with small tweaks, this method could then be used to produce human PGCs shortly after.

But making PGCs for infertility treatment will still be a huge jump, and many scientists — Saitou included — are urging caution. Both iPS and embryonic stem cellsfrequently pick up chromosomal abnormalities, genetic mutations and epigenetic irregularities during culture. “There could be potentially far-reaching, multi-generational consequences if something went wrong in a subtle way,” says Moore.

Proof that the technique is safe in monkeys would help to allay concerns. But how many healthy monkeys would need to be born before the method could be regarded as safe? And how many generations should be observed?

Eventually, human embryos will need to be made and tested, a process that will be slowed by restrictions on creating embryos for research. New, non-invasive imaging techniques will enable doctors to sort good from bad embryos with a high degree of accuracy. Embryos that seem to be similar to normal IVF embryos could get the go-ahead for implantation into humans. This might happen with private funding or in countries with less-restrictive attitudes towards embryo research.

When the technology is ready, even more provocative reproductive feats might be possible. For instance, cells from a man’s skin could theoretically be used to create eggs that are fertilized with a partner’s sperm, then nurtured in the womb of a surrogate. Some doubt, however, that such a feat would ever be possible — the Hinxton Group, an international consortium of scientists that discusses stem-cell ethics and challenges, concluded that it would be difficult to get eggs from male XY cells and sperm from female XX cells. “The instructions that the female niche is supplying to the male cell do not coordinate with each other,” says Clark, a member of the consortium.

Saitou used iPS cells from male mice to create sperm and from female mice to create eggs, but he says that the reverse should be possible. If so, eggs and sperm from the same mouse could be generated and used for fertilization, producing something never seen before: a mouse created by self-fertilization. Neither Hayashi nor Saitou is ready to try this. “We would only do this [in mice] if there were a good scientific reason,” says Saitou. Right now he does not see one.

The two scientists already feel some pressure from patients and Japanese funding agencies to move forward. The technique could be a last hope for women who have had no luck with IVF, or for people who had cancer in childhood and have lost the ability to produce sperm or eggs. Hayashi warns those who write to him that a viable infertility treatment could be 10 or even 50 years in the future. “My impression is that it is very far away. I don’t want to give people unfeasible hope,” he says.

Patients see the end result — success in mice — and often ignore the years of painstaking work that led to such a technical tour de force. They do not realize that switching from mice to humans means starting again almost from scratch, says Hayashi. The human early embryo is so different from the mouse that it is almost “like starting over on a process that took more than ten years”.

Source: Nature. 




Sunless tanning: What you need to know.

Sunless tanning is a practical alternative to sunbathing. Find out how sunless tanning products work, including possible risks and how to get the best results.

Don’t want to expose your skin to the sun’s damaging rays, but still want that sun-kissed glow? Consider trying sunless tanning products. Start by understanding how sunless tanning products work — and the importance of applying them carefully and correctly.

How do sunless tanning products work?

Sunless tanning products, also called self-tanners, can give your skin a tanned look without exposing it to harmful ultraviolet (UV) rays. Sunless tanning products are commonly sold as lotions and sprays you apply to your skin. Professional spray-on tanning also is available at many salons, spas and tanning businesses.

The active ingredient in most sunless tanning products is the color additive, dihydroxyacetone. When applied, dihydroxyacetone reacts with dead cells in the skin’s surface to temporarily darken the skin. The coloring typically wears off after a few days.

Sunless tanning products might or might not contain sunscreen. If a product does contain sunscreen, it will only be effective for a couple of hours. The color produced by the sunless tanning product won’t protect your skin from ultraviolet rays. If you spend time outdoors, sunscreen remains essential.

What about sunless tanning pills?

Sunless tanning pills, which typically contain the color additive canthaxanthin, are unsafe. When taken in large amounts, canthaxanthin can turn your skin orange or brown and cause hives, liver damage and impaired vision.

Is sunless tanning safe?

Topical sunless tanning products are generally considered safe alternatives to sunbathing, as long as they’re used as directed.

The Food and Drug Administration (FDA) has approved dihydroxyacetone for external application to the skin. However, the FDA hasn’t approved the use of dihydroxyacetone for application to areas near the eyes, mouth or nose. If you’re using a sunless tanning lotion, it’s easy to avoid these areas. With spray tanning, this might be more difficult — since the product is usually applied to the whole body to ensure even color. Spray tanning might also cause you to inhale the product.

Further research is needed to determine the risks — if any — of this type of exposure. In the meantime, protect your eyes, mouth and nose when spray tanning and avoid inhaling the product. Be sure to wear goggles and nose plugs, and hold your breath while the spray is being applied.

What’s the best way to apply a sunless tanning lotion?

For best results, follow the package directions carefully. In general:

  • Exfoliate first. Before using a sunless tanning product, wash your skin to remove excess dead skin cells. Spend a little extra time exfoliating areas with thick skin, such as your knees, elbows and ankles.
  • Apply in sections. Massage the product into your skin in a circular motion. Apply the tanner to your body in sections, such as your arms, legs and torso. Wash your hands with soap and water after each section to avoid discoloring your palms. Lightly extend the product from your ankles to your feet and from your wrists to your hands.
  • Wipe joint areas. The knees, elbows and ankles tend to absorb more of sunless tanning products. To dilute the tanning effect in these areas, gently rub them with a damp towel.
  • Take time to dry. Wait to dress at least 10 minutes. Wear loose clothing and avoid sweating for three hours.

Life created from eggs made from skin cells.

Stem cells made from skin have become “grandparents” after generations of life were created in experiments by scientists in Japan.

The cells were used to create eggs, which were fertilised to produce baby mice. These later had their own babies.

If the technique could be adapted for people, it could help infertile couples have children and even allow women to overcome the menopause.

But experts say many scientific and ethical hurdles must be overcome.

Healthy and fertile

Stem cells are able to become any other type of cell in the body from blood to bone, nerves to skin.

Last year the team at Kyoto University managed to make viable sperm from stem cells. Now they have performed a similar feat with eggs.

They used stem cells from two sources: those collected from an embryo and skin-like cells which were reprogrammed into becoming stem cells.

The first step, reported in the journal Science, was to turn the stem cells into early versions of eggs.

A “reconstituted ovary” was then built by surrounding the early eggs with other types of supporting cells which are normally found in an ovary. This was transplanted into female mice.

Surrounding the eggs in this environment helped them to mature.

IVF techniques were used to collect the eggs, fertilise them with sperm from a male mouse and implant the fertilised egg into a surrogate mother.

Dr Katsuhiko Hayashi, from Kyoto University, told the BBC: “They develop to be healthy and fertile offspring.”

Those babies then had babies of their own, whose “grandmother” was a cell in a laboratory dish.

Devastating blow

The ultimate aim of the research is to help infertile couples have children. If the same methods could be used in people then cells in skin could be turned into an egg. Any resulting child would be genetically related to the mother.

However, Dr Hayashi said that was still a distant prospect: “I must say that it is impossible to adapt immediately this system to human stem cells, due to a number of not only scientific reasons, but also ethical reasons.”

He said that the level of understanding of human egg development was still too limited. There would also be questions about the long-term consequences on the health of any resulting child.

Dr Evelyn Telfer, from the University of Edinburgh, said: “It’s an absolutely brilliant paper – they made oocytes [eggs] from scratch and get live offspring. I just thought wow! The science is quite brilliant.”

However, she warned that this had “no clinical relevance” as there were still too many gaps in understanding about how human eggs developed.

“If you can show it works in human cells it is like the Holy Grail of reproductive biology,” she added.

Prof Robert Norman, from the University of Adelaide, said: “For many infertile couples, finding they have no sperm or eggs is a devastating blow.

“This paper offers light to those who want a child, who is genetically related to them, by using personalised stem cells to create eggs that can produce an offspring that appears to be healthy.

“It also offers the potential for women to have their own children well past menopause raising even more ethical issues.

“Application to humans is still a long way off, but for the first time the goal appears to be in sight.”

Dr Allan Pacey, from the British Fertility Society and the University of Sheffield, said: “What is remarkable about this work is the fact that, although the process is still quite inefficient, the offspring appeared healthy and were themselves fertile as adults.”