Lab-grown egg cells could revolutionise fertility and even banish menopause :

Scientists rewrite rules of human reproduction

by Steve CONNOR

The first human egg cells that have been grown entirely in the laboratory from stem cells could be fertilised later this year in a development that will revolutionise fertility treatment and might even lead to a reversal of the menopause in older women. Scientists are about to request a licence from the UK fertility watchdog to fertilise the eggs as part of a series of tests to generate an unlimited supply of human eggs, a breakthrough that could help infertile women to have babies as well as making women as fertile in later life as men.

Producing human eggs from stem cells would also open up the possibility of replenishing the ovaries of older women so that they do not suffer the age-related health problems associated with the menopause, from osteoporosis to heart disease.

Some scientists are even suggesting the possibility of producing an “elixir of youth” for women, where the menopause is eradicated and older women will retain the health they enjoyed when younger.

Researchers at Edinburgh University are working with a team from Harvard Medical School in Boston to be the first in the world to produce mature human eggs from stem cells isolated from human ovarian tissue. Until now, it has only been possible to isolate a relatively small number of mature human egg cells directly from the ovaries of women who have been stimulated with hormones. This technical limitation has led to an acute shortage of human eggs, or “oocycts”, for IVF treatment as well as scientific research.

The scientists want to fertilise the laboratory-grown egg cells with human sperm to prove that they are viable. Any resulting embryos will be studied for up to 14 days - the legal limit - to see if they are normal.

These early embryos will not be transplanted into a woman's womb because they will be deemed experimental material, but will either be frozen or allowed to perish.

Evelyn Telfer, a reproductive biologist at Edinburgh University, has already informally approached the Human Fertilisation and Embryology Authority (HFEA) with a view to submitting a formal licence application within the next few weeks.

“We hope to apply for a research licence to do the fertilisation of the in vitro grown oocytes within the IVF unit at the Edinburgh Royal Infirmary,” Dr Telfer said.

“Could the fertilisation take place this year? Yes, absolutely,” she said. Professor Richard Anderson of the MRC Centre for Reproductive Health, who will be in charge of the clinical aspects of the work, said: “The aim will be to demonstrate that the eggs that we’ve generated in vitro are competent to form embryos and that’s the best test that an egg is an egg,”

Generating an unlimited supply of human eggs and the prospect of reversing the menopause was made possible by a series of breakthroughs led by Professor Jonathan Tilly of Harvard.

In 2004, he astounded the world of reproductive biology by suggesting that there were active stem cells in the ovaries of mice that seemed capable of replenishing eggs throughout life.

For half a century, a dogma of reproductive biology was that women are born with their full complement of egg cells which they gradually lose through life until they run out when they reach the menopause.

“This age-old belief that females are given a fixed ‘bank account’ of eggs at birth is incorrect,” Professor Tilly said.

“In fact ovaries in adulthood are probably more closely matched to testes in adulthood in their capacity to make new germ cells, which are the special cells that give rise to sperm and eggs,“ he said.

”Over the past 50 years, all the basic science, all the clinical work and all the clinical outcome was predicated on one simple belief, that is the oocyte pool, the early egg-cell pool in the ovaries was a fixed entity, and once those eggs were used up they cannot be renewed, replenished or replaced,“ he added.

Last month, Prof Tilly published pioneering research showing that these stem cells exist in human ovaries and that they could be stimulated in the laboratory to grow into immature egg cells.

He is collaborating with Dr Telfer, who was once sceptical of his research, because in Edinburgh she has pioneered a technique for growing immature eggs cells to the fully “ripened” stage when they can be fertilised.

”It's been fun to work with her because she's been one of the most vocal critics of this work years ago and it's great that she's come about and changed her views,“ Prof Tilly said.

”I think personally [fertilising the first eggs] is do-able. I see no hurdles why it cannot be done this year,“ he said.

Dr Telfer added: “The important thing is that if you can show you can get ovarian stem cells from human ovary you then have the potential to do more for fertility preservation.

“We have all the local ethical approval in place and we’re now looking at the process of the HFEA application. There is a push for us to do it now,” she added.

The Independent

The mystery of human consciousness

A wakening from anesthesia is often associated with an initial phase of delirious struggle before the full restoration of awareness and orientation to one's surroundings. Scientists now know why this may occur: primitive consciousness emerges first. Using brain imaging techniques in healthy volunteers, a team of scientists led by Adjunct Prof Harry Scheinin, M.D. from the University of Turku, Turku, Finland in collaboration with investigators from the University of California, Irvine, USA, have now imaged the process of returning consciousness after general anesthesia. The emergence of consciousness was found to be associated with activations of deep, primitive brain structures rather than the evolutionary younger neocortex.

These results may represent an important step forward in the scientific explanation of human consciousness. The study was part of the Research Program on Neuroscience by the Academy of Finland. “We expected to see the outer bits of brain, the cerebral cortex (often thought to be the seat of higher human consciousness), would turn back on when consciousness was restored following anesthesia. Surprisingly, that is not what the images showed us. In fact, the central core structures of the more primitive brain structures including the thalamus and parts of the limbic system appeared to become functional first, suggesting that a foundational primitive conscious state must be restored before higher order conscious activity can occur” Scheinin said.

Twenty young healthy volunteers were put under anesthesia in a brain scanner using either dexme-detomidine or propofol anesthetic drugs. The subjects were then woken up while brain activity pictures were being taken. Dexmedetomidine is used as a sedative in the intensive care unit setting and propofol is widely used for induction and maintenance of general anesthesia.

Dexmedetomidineinduced unconsciousness has a close resemblance to normal physiological sleep, as it can be reversed with mild physical stimulation or loud voices without requiring any change in the dosing of the drug. This unique property was critical to the study design, as it enabled the investigators to separate the brain activity changes associated with the changing level of consciousness from the drugrelated effects on the brain. The staterelated changes in brain activity were imaged with positron emission tomography (PET).

The emergence of consciousness, as assessed with a motor response to a spoken command, was associated with the activation of a core network involving subcortical and limbic regions that became functionally coupled with parts of frontal and inferior parietal cortices upon awakening from dexme-detomidine-induced unconsciousness. This network thus enabled the subjective awareness of the external world and the capacity to behaviorally express the contents of consciousness through voluntary responses.

Interestingly, the same deep brain structures, i.e. the brain stem, thalamus, hypothalamus and the anterior cingulate cortex, were activated also upon emergence from propofol anesthesia, suggesting a common, drugindependent mechanism of arousal. For both drugs, activations seen upon regaining consciousness were thus mostly localized in deep, phylogenetically old brain structures rather than in the neocortex. The researchers speculate that because current depth-of-anesthesia monitoring technology is based on cortical electroencephalography (EEG) measurement (i.e., measuring electrical signals on the sur-face of the scalp that arise from the brain's cortical surface), their results help to explain why these devices fail in differentiating the conscious and unconscious states and why patient awareness during general anesthesia may not always be detected. The results presented here also add to the current understanding of anesthesia mechanisms and form the foundation for developing more reliable depth-of-anesthesia technology.

The anesthetised brain provides new views into the emergence of consciousness. Anesthetic agents are clinically useful for their remarkable property of being able to manipulate the state of consciousness. When given a sufficient dose of an anesthetic, a person will lose the precious but mysterious capacity of being aware of one's own self and the surrounding world, and will sink into a state of oblivion. Conversely, when the dose is lightened or wears off, the brain almost magically recreates a subjective sense of being as experience and awareness returns. The ultimate nature of consciousness remains a mystery, but anesthesia offers a unique window for imaging internal brain activity when the subjective phenomenon of consciousness first vanishes and then re-emerges. This study was designed to give the clearest picture so far of the internal brain processes involved in this phenomenon.

The results may also have broader implications. The demonstration of which brain mechanisms are involved in the emergence of the conscious state is an important step forward in the scientific explanation of consciousness. Yet, much harder questions remain. How and why do these neural mechanisms create the subjective feeling of being, the awareness of self and environment the state of being conscious?

NYT

A link between atherosclerosis and autoimmunity

Those who suffer from autoimmune diseases also display a tendency to develop atherosclerosis - the condition popularly known as hardening of the arteries. Clinical researchers at LMU, in collaboration with colleagues in Würzburg, have now discovered a mechanism which helps to explain the connection between the two types of disorder.

The link is provided by a specific class of immune cells called plasmacytoid dendritic cells (pDCs). pDCs respond to DNA released from damaged and dying cells by secreting interferon proteins which stimulate the immune reactions that underlie autoimmune diseases. The new study shows that stimulation of pDCs by a specific DNA-protein complex contributes to the progression of atherosclerosis.

Implications

The findings may have implications for new strategies for the treatment of a whole spectrum of conditions that are associated with chronic inflammatory reactions. Atherosclerosis is a major cause of death in Western societies. The illness is due to the formation of insoluble deposits called atherosclerotic plaques on the walls of major arteries as a consequence of chronic, localised inflammation reactions.

By reducing blood flow, the plaques can provoke heart attacks and strokes. A class of immune cells called dendritic cells plays a crucial role in facilitating the development of these plaques. The term refers to a heterogeneous cell population that makes up part of the immune system. Among the cell types represented in this population are the so-called plasmacytoid dendritic cells (pDC), but their potential significance for atherosclerosis had not been explored until now.

Disorders

A group of researchers led by Dr. Yvonne Döring in Prof Christian Weber's department at LMU, together with a team supervised by Privatdozentin Dr. Alma Zernecke of Würzburg University, has now shown how pDCs promote the development of atherosclerosis – and explained why patients with autoimmune disorders, such as psoriasis or systemic lupus (SLE), show a predisposition to atherosclerosis.

Using laboratory mice as an experimental model, the researchers were able to show that pDCs contribute to early steps in the formation of athersclerotic lesions in the blood vessels. Stimulation of pDCs causes them to secrete large amounts of interferons, proteins that strongly stimulate inflammatory processes. The protein that induces the release of interferons is produced by immune cells that accumulate specifically at sites of inflammation, and mice that are unable to produce this protein also have fewer plaques. Stimulation of pDCs in turn leads to an increase in the numbers of macrophages present in plaques. Macrophages normally act as a clean-up crew, removing cell debris and fatty deposits by ingesting and degrading them.

However, they can also “overindulge”, taking up more fat than they can digest. When this happens, they turn into so-called foam cells that promote rather than combat atherosclerosis. In addition, activated, mature pDCs can initiate an immune response against certain molecules found in atherosclerotic lesions, which further exacerbates the whole process.

Disorders

The disorders of pDCs provides the link between atherosclerosis and autoimmune diseases. “The pDCs themselves are stimulated by the self-antigens that set off the autoimmune reactions which result in conditions like psoriasis and SLE,” says Döring. Indeed, it is well known that the secretion of interferons by activated pDCs contributes to the genesis of a number of autoimmune diseases

“The findings also suggest new approaches to the treatment of chronic inflammation that could be useful for a whole range of diseases,” said Webber.

MNT

Enzyme in saliva helps regulate blood glucose

Scientists from the Monell Center report that blood glucose levels following starch ingestion are influenced by genetically determined differences in salivary amylase, an enzyme that breaks down dietary starches. Specifically, higher salivary amylase activity is related to lower blood glucose.

The findings are the first to demonstrate a significant metabolic role for salivary amylase in starch digestion, suggesting that this oral enzyme may contribute significantly to overall metabolic status. Other implications relate to calculating the glycemic index of starch-rich foods and ultimately the risk of developing diabetes “Two individuals may have very different glycemic responses to the same starchy food, depending on their amylase levels,” said lead author Abigail Mandel, Ph.D., a nutritional scientist at Monell.

“Those with high amylase levels are better adapted to eat starches, as they rapidly digest the starch while maintaining balanced blood glucose levels. The opposite is true for those with low amylase levels.

As such, people may want to take their amylase levels into account if they are paying attention to the glycemic index of the foods they are eating.” Starch from wheat, potatoes, corn, rice, and other grains is a major component of the United States diet, comprising up to 60 percent of our calories. Amylase enzymes secreted in saliva help break down starches into simpler sugar molecules that can be absorbed into the bloodstream. In this way, amylase activity influences blood glucose levels, which need to be maintained within an optimal range for good health.

Starch

A previous study had demonstrated that individuals with high salivary amylase activity are able to break down oral starch very rapidly. This finding led the researchers to ask how this ‘pre-digestion’ contributes to overall starch digestion and glucose metabolism.

In the current study, published online in *The Journal of Nutrition*, amylase activity was measured in saliva samples obtained from 48 healthy adults. Based on extremes of salivary amylase activity, two groups of seven were formed: high amylase (HA) and low amylase (LA). Each subject drank a simplified corn starch solution and blood samples were obtained over a two hour period afterwards. The samples were analysed to determine blood glucose levels and insulin concentrations.

After ingesting the starch, individuals in the HA group had lower blood glucose levels relative to those in the LA group. This appears to be related to an early release of insulin by the HA individuals.

“Not all people are the same in their ability to handle starch,” said senior author Paul Breslin, Ph.D., a sensory geneticist at Monell.

“People with higher levels of salivary amylase are able to maintain more stable blood glucose levels when consuming starch.

This might ultimately lessen their risk for insulin resistance and non-insulin dependent diabetes.”

Additional studies will confirm the current findings using more complex starchy foods, such as bread and pasta. Another focus will involve identifying the neuroendocrine mechanisms that connect starch breakdown in the mouth with insulin release.

- Medicalxpress