induced pluripotent stem cell | The Science of Parkinson’s

Parkinsons is a neurodegenerative condition. This means that cells in the brain are being lost over time. Any cure for Parkinsons is going to require some form of cell replacement therapy introducing new cells that can replace those that were lost.

Cell transplantation represents one approach to cell replacement therapy, and this week we learned that the Japanese regulatory authorities have given the green light for a new cell transplantation clinical trial to take place in Kyoto.

This new trial will involve cells derived from induced pluripotent stem cells (or IPS cells).

Intodays post we will discuss whatinduced pluripotent stem cells are, what previous research has been conducted on these cells, and what we know about the new trial.

Source:Glastone Institute

The man in the image above is ProfShinya Yamanaka.

Hes a rockstar in the biomedical research community.

ProfYamanaka is the director ofCenter forinduced Pluripotent Stem CellResearch and Application(CiRA); and a professor at theInstitute for Frontier Medical SciencesatKyoto University.

But more importantly, in 2006 he published a research report that would quite literally change everything.

In that report, he demonstrated a method by which someonecould take a simple skin cell (called a fibroblast), grow it in cell culture for a while, and then re-programit so that it would transform into a stem cell a cell that is capable of becoming any kind of cell in the body.

The transformed cells were calledinduced pluripotent stem (IPS) cell pluripotent meaning capable of any fate.

It was an amazing feat that made the hypothetical idea of personalised medicine suddenly very possible take skin cells from anyone with a particular medical condition, turn them into whatever cell type you like, and then either test drugs on those cells or transplant them back into their body (replacing the cells that have been lost due to the medical condition).

Personalised medicine with IPS cells. Source:Bodyhacks

IPS cells are now being used all over the world, for all kinds of biomedical research. And many research groups are rushing to bring IPS cell-based therapies to the clinic in the hope of providing the long sort-after dream of personalised medicine.

This week the Parkinsons community received word that the Pharmaceuticals and Medical Devices Agency (PMDA) the Japanese regulatory agency that oversees clinical trials have agreed for researchers at Kyoto University to conduct a cell transplantation trial for Parkinsons, using dopamine neurons derived from IPS cells. And the researchers are planning to begin their study in the next month.

In todays post we are going to discuss this exciting development, but we should probably start at the beginning with the obvious question:

What exactly is an IPS cell?

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New research provides some interesting insight into particular cellular functions and possibly sleep issues associated with Parkinsons.

Researchers in Belgium have recently published interesting findings that a genetic model of Parkinsons exhibits sleep issues, which are not caused by neurodegeneration, but rather neuronal dysfunction. And as a result, they were able to treat it in flies at least.

In todays post, we will review this new research and consider its implications.

Source:Dlanham

I am a night owl.

One that is extremely reluctant to give up each day to sleep. There is always something else that can be done before going to bed. And I can often be found pottering around at 1 or 2am on a week night.

As a result of this foolish attitude, I am probably one of the many who live in a state of sleep deprivation.

I am a little bit nervous about doing the spoon test:

But I do understand that sleep is very important for our general level of health and well being. And as a researcher on the topic, I know that sleep complications can be a problem for people with Parkinsons.

What sleep issues are there for people with Parkinsons?

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This week a group of scientists have published an article which indicates differences between mice and human beings, calling into question the use of these mice in Parkinsons disease research.

The results could explain way mice do not get Parkinsons disease, and theymay also partly explain why humans do.

In todays post we will outline the new research, discuss the results, and look at whether Levodopa treatment may (or may not) be a problem.

The humble lab mouse. Source: PBS

Much of our understanding of modern biology is derived from the lower organisms.

From yeast to snails (there is a post coming shortly on a snail model of Parkinsons disease I kid you not) and from flies to mice, a great deal of what we know about basic biology comes from experimentation on these creatures. So much in fact that many of our current ideas about neurodegenerative diseases result from modelling those conditions in these creatures.

Now say what you like about the ethics and morality of this approach, these organisms have been useful until now. And I say until now because an interesting research report was released this week which may call into question much of the knowledge we have from the modelling of Parkinsons disease is these creatures.

You see, heres the thing: Flies dont naturally develop Parkinsons disease.

Nor do mice. Or snails.

Or yeast for that matter.

So we are forcing a very un-natural state upon the biology of these creatures and then studying the response/effect. Which could be giving us strange results that dont necessarily apply to human beings. And this may explain our long history of failed clinical trials.

We work with the best tools we have, but it those tools are flawed

What did the new research report find?

This is the study:

Title: Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinsons disease Authors: Burbulla LF, Song P, Mazzulli JR, Zampese E, Wong YC, Jeon S, Santos DP, Blanz J, Obermaier CD, Strojny C, Savas JN, Kiskinis E, Zhuang X, Krger R, Surmeier DJ, Krainc D Journal: Science, 07 Sept 2017 Early online publication PMID:28882997

The researchers who conducted this study began by growing dopamine neurons a type of cell badly affected by Parkinsons disease from induced pluripotent stem (IPS) cells.

What are induced pluripotent stem cells?

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Two months ago a research report was published in the scientific journal Nature and it caused a bit of a fuss in the embryonic stem cell world.

Embryonic stem (ES) cells are currently being pushed towards the clinic as a possible source of cells for regenerative medicine. But this new report suggested that quite a few of the embryonic stem cells being tested may be carrying genetic variations that could be bad. Bad as in cancer bad.

In this post, I will review the study and discuss what it means for cell transplantation therapy for Parkinsons disease.

Source: Medicalexpress

For folks in the stem cell field, the absolute go-to source for all things stem cell related isProf Paul Knoepflers blog The Niche. From the latest scientific research to exciting new stem cell biotech ventures (and even all of the regulatory changes being proposed in congress), Pauls blog is a daily must read for anyone serious about stem cell research. He has his finger on the pulse and takes the whole field very, very seriously.

Prof Paul Knoepfler during his TED talk.Source: ipscell

For a long time now, Paul has been on a personal crusade. Like many others in the field (including yours truly), he has been expressing concern about the unsavoury practices of the growing direct-to-consumer, stem cell clinic industry. You may have seen him mentioned in the media regarding this topic (such as this article).

The real concern is that while much of the field is still experimental, many stem cell clinics are making grossly unsubstantiated claims to draw in customers. From exaggerated levels of successful outcomes (100% satisfaction rate?) all the way through to talking about clinical trials that simply do not exist.The industry is badly (read: barely) regulated which is ultimately putting patients at risk (one example: three patients were left blind after undergoing an unproven stem cell treatment click here to read more on this).

While the stem cell research field fully understands and appreciates the desperate desire of the communities affected by various degenerative conditions, there has to be regulations and strict control standards that all practitioners must abide by. And first amongst any proposed standards should be that the therapy has been proven to be effective for a particular condition in independently audited double blind, placebo controlled trials. Until such proof is provided, the sellers of such products are simply preying on the desperation of the people seeking these types of procedures.

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Last weekscientists in Sweden published researchdemonstrating a method by which the supportive cells of the brain (called astrocytes) can be re-programmed into dopamine neurons in the brain of a live animal!

It was a reallyimpressive trick and it could have major implications for Parkinsons disease.

In todays post is a long read, but in it we will review the research leading up to the study, explain the science behindthe impressive feat, and discuss where things go from here.

Different types of cells in the body. Source: Dreamstime

In your body at this present moment in time, there is approximately 40 trillion cells (Source).

The vast majority of those cells have developedinto mature types of cell and they are undertaking veryspecific functions. Muscle cells, heart cells, brain cells all working together in order to keep you verticaland ticking.

Now, once upon a time we believed that the maturation (or the more technical term: differentiation) of a cell was a one-way street. That is to say, once acellbecame what it was destined to become, there was no going back. This was biological dogma.

Then aguy in Japan did something rather amazing.

Who is he and what did he do?

This is ProfShinya Yamanaka:

ProfShinya Yamanaka. Source: Glastone Institute

Hes a rockstar in the scientific research community.

ProfYamanaka is the director of Center for induced Pluripotent Stem Cell Research and Application(CiRA); and a professor at theInstitute for Frontier Medical Sciences at Kyoto University.

But more importantly, in 2006 he published a research reportdemonstrating how someonecould take a skin cell and re-programit so that was now a stem cell capable of becoming any kind of cell in the body.

Heres the study:

Title: Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Authors: Takahashi K, Yamanaka S. Journal: Cell. 2006 Aug 25;126(4):663-76. PMID: 16904174 (This article is OPEN ACCESS if you would like to read it)

Shinya Yamanakas team started with the hypothesis that genes which are important to the maintenance of embryonic stem cells (the cells that give rise to all cells in the body) might also be able to cause an embryonic state in mature adult cells. They selected twenty-four genes that had been previously identified as important in embryonic stem cells to test this idea. They used re-engineered retroviruses to deliver these genes to mouse skin cells. The retroviruses were emptied of all their disease causing properties, and could thus function as very efficient biological delivery systems.

The skin cells were engineered so that only cells in which reactivation of the embryonic stem cells-associated gene, Fbx15, would survive the testing process. If Fbx15 was not turned on in the cells, they would die. When the researchers infected the cells with all twenty-four embryonic stem cells genes, remarkably some of the cells survived and began to divide like stem cells.

In order to identify the genes necessary for the reprogramming, the researchers began removing one gene at a time from the pool of twenty-four. Through this process, they were able to narrow down the most effective genes to justfour: Oct4, Sox2, cMyc, and Klf4, which became known as the Yamanaka factors.

This new type of cell is called an induced pluripotent stem (IPS) cell pluripotent meaning capable of any fate.

The discovery of IPS cells turned biological dogma on its head.

And in acknowledgement of this amazing bit of research, in 2012 ProfYamanaka and Prof John Gurdon (University of Cambridge)were awarded the Nobel prize for Physiology and Medicinefor the discovery that mature cells can be converted back to stem cells.

Prof Yamanaka and Prof Gurdon. Source: UCSF

Prof Gurdon achieved the feat in 1962 when he removed the nucleus of a fertilised frog egg cell and replaced it with the nucleus of a cell taken from a tadpoles intestine. The modified egg cell then grew into an adult frog! This fascinatingresearchproved that the mature cell still contained the genetic information needed to form all types of cells.

EDITORS NOTE: We do not want to be accused of taking anything away from Prof Gurdons contribution to this field (which was great!) by not mentioning his efforts here. For the sake of saving time and space, we are focusing onProf Yamanakas research as it is more directly related to todays post.

Making IPS cells. Source: learn.genetics

Link:
induced pluripotent stem cell | The Science of Parkinson's

Menstrual cycle – Wikipedia

The menstrual cycle is the regular natural change that occurs in the female reproductive system (specifically the uterus and ovaries) that makes pregnancy possible.[1][2] The cycle is required for the production of oocytes, and for the preparation of the uterus for pregnancy.[1] Up to 80% of women report having some symptoms during the one to two weeks prior to menstruation.[3] Common symptoms include acne, tender breasts, bloating, feeling tired, irritability and mood changes.[4] These symptoms interfere with normal life and therefore qualify as premenstrual syndrome in 20 to 30% of women. In 3 to 8%, they are severe.[3]

The first period usually begins between twelve and fifteen years of age, a point in time known as menarche.[5] They may occasionally start as early as eight, and this onset may still be normal.[6] The average age of the first period is generally later in the developing world and earlier in developed world. The typical length of time between the first day of one period and the first day of the next is 21 to 45 days in young women and 21 to 35 days in adults (an average of 28 days[6][7][8]). Menstruation stops occurring after menopause which usually occurs between 45 and 55 years of age.[9] Bleeding usually lasts around 2 to 7 days.[6]

The menstrual cycle is governed by hormonal changes.[6] These changes can be altered by using hormonal birth control to prevent pregnancy.[10] Each cycle can be divided into three phases based on events in the ovary (ovarian cycle) or in the uterus (uterine cycle).[1] The ovarian cycle consists of the follicular phase, ovulation, and luteal phase whereas the uterine cycle is divided into menstruation, proliferative phase, and secretory phase.

Stimulated by gradually increasing amounts of estrogen in the follicular phase, discharges of blood (menses) flow stop, and the lining of the uterus thickens. Follicles in the ovary begin developing under the influence of a complex interplay of hormones, and after several days one or occasionally two become dominant (non-dominant follicles shrink and die). Approximately mid-cycle, 2436 hours after the luteinizing hormone (LH) surges, the dominant follicle releases an ovocyte, in an event called ovulation. After ovulation, the ovocyte only lives for 24 hours or less without fertilization while the remains of the dominant follicle in the ovary become a corpus luteum; this body has a primary function of producing large amounts of progesterone. Under the influence of progesterone, the uterine lining changes to prepare for potential implantation of an embryo to establish a pregnancy. If implantation does not occur within approximately two weeks, the corpus luteum will involute, causing a sharp drop in levels of both progesterone and estrogen. The hormone drop causes the uterus to shed its lining in a process termed menstruation. Menstruation also occurs in closely related primates (apes and monkeys).[11]

The average age of menarche is 1215.[5][12] They may occasionally start as early as eight, and this onset may still be normal.[6] This first period often occurs later in the developing world than the developed world.[8]

The average age of menarche is approximately 12.5 years in the United States,[13] 12.7 in Canada,[14] 12.9 in the UK[15] and 13.1 years in Iceland.[16] Factors such as genetics, diet and overall health can affect timing.[17]

The cessation of menstrual cycles at the end of a woman's reproductive period is termed menopause. The average age of menopause in women is 52 years, with anywhere between 45 and 55 being common. Menopause before age 45 is considered premature in industrialised countries.[18] Like the age of menarche, the age of menopause is largely a result of cultural and biological factors;[19] however, illnesses, certain surgeries, or medical treatments may cause menopause to occur earlier than it might have otherwise.[20]

The length of a woman's menstrual cycle typically varies somewhat, with some shorter cycles and some longer cycles. A woman who experiences variations of less than eight days between her longest cycles and shortest cycles is considered to have regular menstrual cycles. It is unusual for a woman to experience cycle length variations of more than four days. Length variation between eight and 20 days is considered as moderately irregular cycles. Variation of 21 days or more between a woman's shortest and longest cycle lengths is considered very irregular. [21]

The average menstrual cycle lasts 28 days. The variability of menstrual cycle lengths is highest for women under 25 years of age and is lowest, that is, most regular, for ages 25 to 39.[7] Subsequently, the variability increases slightly for women aged 40 to 44.[7]

The luteal phase of the menstrual cycle is about the same length in most individuals (mean 14.13 days, standard deviation 1.41 days)[22] whereas the follicular phase tends to show much more variability (log-normally distributed with 95% of individuals having follicular phases between 10.3 and 16.3 days).[23] The follicular phase also seems to get significantly shorter with age (geometric mean 14.2 days in women aged 1824 vs. 10.4 days in women aged 4044).[23]

Some women with neurological conditions experience increased activity of their conditions at about the same time during each menstrual cycle. For example, drops in estrogen levels have been known to trigger migraines,[24] especially when the woman who suffers migraines is also taking the birth control pill. Many women with epilepsy have more seizures in a pattern linked to the menstrual cycle; this is called "catamenial epilepsy".[25] Different patterns seem to exist (such as seizures coinciding with the time of menstruation, or coinciding with the time of ovulation), and the frequency with which they occur has not been firmly established. Using one particular definition, one group of scientists found that around one-third of women with intractable partial epilepsy has catamenial epilepsy.[25][26][27] An effect of hormones has been proposed, in which progesterone declines and estrogen increases would trigger seizures.[28] Recently, studies have shown that high doses of estrogen can cause or worsen seizures, whereas high doses of progesterone can act like an antiepileptic drug.[29] Studies by medical journals have found that women experiencing menses are 1.68 times more likely to attempt suicide.[30]

Mice have been used as an experimental system to investigate possible mechanisms by which levels of sex steroid hormones might regulate nervous system function. During the part of the mouse estrous cycle when progesterone is highest, the level of nerve-cell GABA receptor subtype delta was high. Since these GABA receptors are inhibitory, nerve cells with more delta receptors are less likely to fire than cells with lower numbers of delta receptors. During the part of the mouse estrous cycle when estrogen levels are higher than progesterone levels, the number of delta receptors decrease, increasing nerve cell activity, in turn increasing anxiety and seizure susceptibility.[31]

Estrogen levels may affect thyroid behavior.[32] For example, during the luteal phase (when estrogen levels are lower), the velocity of blood flow in the thyroid is lower than during the follicular phase (when estrogen levels are higher).[33]

Among women living closely together, it was once thought that the onsets of menstruation tend to synchronize. This effect was first described in 1971, and possibly explained by the action of pheromones in 1998.[34] Subsequent research has called this hypothesis into question.[35]

Research indicates that women have a significantly higher likelihood of anterior cruciate ligament injuries in the pre-ovulatory stage, than post-ovulatory stage.[36]

The most fertile period (the time with the highest likelihood of pregnancy resulting from sexual intercourse) covers the time from some 5 days before until 1 to 2 days after ovulation.[38] In a 28day cycle with a 14day luteal phase, this corresponds to the second and the beginning of the third week. A variety of methods have been developed to help individual women estimate the relatively fertile and the relatively infertile days in the cycle; these systems are called fertility awareness.

There are many fertility testing methods, including urine test kits that detect the LH surge that occurs 24 to 36 hours before ovulation; these are known as ovulation predictor kits (OPKs).[39] Computerized devices that interpret basal body temperatures, urinary test results, or changes in saliva are called fertility monitors. Fertility awareness methods that rely on cycle length records alone are called calendar-based methods.[40] Methods that require observation of one or more of the three primary fertility signs (basal body temperature, cervical mucus, and cervical position)[41] are known as symptoms-based methods.[40]

A woman's fertility is also affected by her age.[42] As a woman's total egg supply is formed in fetal life,[43] to be ovulated decades later, it has been suggested that this long lifetime may make the chromatin of eggs more vulnerable to division problems, breakage, and mutation than the chromatin of sperm, which are produced continuously during a man's reproductive life. However, despite this hypothesis, a similar paternal age effect has also been observed.

As measured on women undergoing in vitro fertilization, a longer menstrual cycle length is associated with higher pregnancy and delivery rates, even after age adjustment.[44]Delivery rates after IVF have been estimated to be almost doubled for women with a menstrual cycle length of more than 34 days compared with women with a menstrual cycle length shorter than 26 days.[44] A longer menstrual cycle length is also significantly associated with better ovarian response to gonadotropin stimulation and embryo quality.[44]

The different phases of the menstrual cycle correlate with women's moods. In some cases, hormones released during the menstrual cycle can cause behavioral changes in females; mild to severe mood changes can occur.[45] The menstrual cycle phase and ovarian hormones may contribute to increased empathy in women. The natural shift of hormone levels during the different phases of the menstrual cycle has been studied in conjunction with test scores. When completing empathy exercises, women in the follicular stage of their menstrual cycle performed better than women in their midluteal phase. A significant correlation between progesterone levels and the ability to accurately recognize emotion was found. Performances on emotion recognition tasks were better when women had lower progesterone levels. Women in the follicular stage showed higher emotion recognition accuracy than their midluteal phase counterparts. Women were found to react more to negative stimuli when in midluteal stage over the women in the follicular stage, perhaps indicating more reactivity to social stress during that menstrual cycle phase.[46] Overall, it has been found that women in the follicular phase demonstrated better performance in tasks that contain empathetic traits.

Fear response in women during two different points in the menstrual cycle has been examined. When estrogen is highest in the preovulatory stage, women are significantly better at identifying expressions of fear than women who were menstruating, which is when estrogen levels are lowest. The women were equally able to identify happy faces, demonstrating that the fear response was a more powerful response. To summarize, menstrual cycle phase and the estrogen levels correlates with womens fear processing.[47]

However, the examination of daily moods in women with measuring ovarian hormones may indicate a less powerful connection. In comparison to levels of stress or physical health, the ovarian hormones had less of an impact on overall mood.[48] This indicates that while changes of ovarian hormones may influence mood, on a day-to-day level it does not influence mood more than other stressors do.

Sexual feelings and behaviors change during the menstrual cycle. Before and during ovulation, high levels of estrogen and androgens result in women having an increased interest in sexual activity.[49] Unlike other animal species, women show interest in sex across all days of the menstrual cycle, regardless of fertility.[50]

Behavior towards potential mating partners changes during different phases of the menstrual cycle.[51][52][53] Near ovulation, women may have increased physical attraction and interest in attending social gatherings with men.[54] During the fertile phase of the cycle, women appear to prefer males who are more masculine.[55] The intensity of mate guarding differs across the phases of the cycle, with increased mate guarding occurring when women are fertile.[53][56][57]

During the fertile phase, many women experience more attraction, fantasies and sexual interest for extra pair men but not for the primary partner.[54][53][58] They also engage in extra-pair flirtations and demonstrate a preference for extra pair copulation.[54][58]

Preferences for voice pitch change across the cycle.[58] When seeking a short term mating partner, women may prefer a male with a low voice pitch, particularly during the fertile phase.[58] During the late follicular phase, it is common for women demonstrate a preference for mates with a masculine, deep voice.[59] Research has also been conducted on the attractiveness of the female voice throughout the cycle.[60] During their most fertile phase of the menstrual cycle, there is some evidence that female voices are rated as significantly more attractive.[60] This effect is not found with women on the birth control pill.[60]

Women's preference for male's body odor can change across the menstrual cycle.[61] Males who score highly on dominance have been rated as sexier by females during the fertile phase of the menstrual cycle. Additionally, during their most fertile phase of the menstrual cycle, women may show preference for the odor of symmetrical men.[53] This effect is not found for women on the birth control pill.[62] Also, during the late follicular and ovulatory phases, women prefer the scent of masculine men.[58] The scent of androsterone (responsible for testosterone levels) is highly preferred by women during the peak of their fertility in the menstrual cycle.[58] Moreover, women may demonstrate preference for men with a scent that indicates developmental stability.[58]

With regard to women's smell across the cycle, some evidence indicates that men use olfactory cues in order to know if a woman is ovulating.[61] Using a rating of women's odors, women who are ovulating have been rated as more attractive by men.[61] Men demonstrate preferences for the scent of fertile women.[61]

Preferences for facial features in mates can also change across the cycle.[58] There has been no difference found in preference for long-term mating partners during the menstrual cycle; however, those seeking a short-term relationship were more likely to choose a partner with more masculine features than usual.[54][59] This was found to be the case especially during the woman's high conception risk stage and when salivary testosterone was high.[63] However, when women are in the luteal (non-fertile) phase, they tend to prefer men (and females) with more feminine faces.[59] A preference is also shown for self-resembling faces and apparent health in faces during the luteal phase of the cycle.[64] Apparent health preferences were found to be strongest when progesterone levels were high.[64] Additionally, during the fertile phase, many women show a preference for men with darker skin pigmentation.[58] Research on facial symmetry is mixed.[65]

Preferences for body features can change during the fertile phase of the cycle. Women seeking a short-term partner demonstrate a preference for taller and muscular males.[58] Women also show preferences of males with masculine bodies at peak fertility.[58][63] Mixed research has been found regarding body symmetry preferences throughout different phases of the cycle.[58]

In short term mates, during the fertile phase, women may show more attraction to dominant men who display social presence.[58] For long-term mates, shifts in desired trait preferences do not occur throughout the cycle.[58]

Females have been found to experience different eating habits at different stages of their menstrual cycle, with food intake being higher during the luteal phase than the follicular phase.[66][67] Food intake increases by approximately 10% during the luteal phase compared to the follicular phase.[67]

Various studies have shown that during the luteal phase woman consume more carbohydrates, proteins and fats and that 24-hour energy expenditure shows increases between 2.5-11.5%.[68] The increasing intake during the luteal phase may be related to higher preferences for sweet and fatty foods, which occurs naturally and is enhanced during the luteal phases of the menstrual cycle.[68] This is due to the higher metabolic demand during this phase.[69] In particular, women tend to show a cravings for chocolate, with higher cravings during the luteal phase.[68]

Females with premenstrual syndrome (PMS) report changes in appetite across the menstrual cycle more than non-sufferers of PMS, possibly due to their oversensitivity to changes in hormone levels.[67] In women with PMS, food intake is higher in the luteal phase than follicular.[70] The remaining symptoms of PMS, including mood changes and physical symptoms, also occur during the luteal phase. No difference for preference of food types has been found between PMS sufferers and non-sufferers.[66]

The different levels of ovarian hormones at different stages of the cycle have been used to explain eating behaviour changes. Progesterone has been shown to promote fat storage, causing a higher intake of fatty foods during the luteal phase when progesterone levels are higher.[67] Additionally, with a high estrogen level dopamine is ineffective in converting to noradrenaline, a hormone which promotes eating, therefore decreasing appetite.[67] In humans, the level of these ovarian hormones during the menstrual cycle have been found to influence binge eating.[71]

It is theorized that the use of birth control pills should affect eating behaviour as they minimise or remove the fluctuations in hormone levels.[66] The neurotransmitter serotonin is also thought to play a role in food intake. Serotonin is responsible for inhibiting eating and controlling meal size,[72] among other things, and is modulated in part by ovarian hormones.[73]

A number of factors affect whether dieting will affect these menstrual processes: age, weight loss and the diet itself. First, younger women are likely to experience menstrual irregularities due to their diet. Second, menstrual abnormalities are more likely with more weight loss. For example, anovulatory cycles can occur as a result of adopting a restricted diet, as well as engaging in a high amount of exercise.[67] Finally, the cycle is affected more by a vegetarian diet compared to a non-vegetarian diet.[74]

Studies investigating effects of the menstrual cycle on alcohol consumption have found mixed evidence.[75] However, some evidence suggests that individuals consume more alcohol during the luteal stage, especially if these individuals are heavy drinkers or have a family history of alcohol abuse.[69]

The level of substance abuse increases with PMS, mostly with addictive substances such as nicotine, tobacco and cocaine.[69] One theory behind this suggests this higher level of substance abuse is due to decreased self-control as a result of the higher metabolic demands during the luteal phase.[69]

Infrequent or irregular ovulation is called oligoovulation.[76] The absence of ovulation is called anovulation. Normal menstrual flow can occur without ovulation preceding it: an anovulatory cycle. In some cycles, follicular development may start but not be completed; nevertheless, estrogens will be formed and stimulate the uterine lining. Anovulatory flow resulting from a very thick endometrium caused by prolonged, continued high estrogen levels is called estrogen breakthrough bleeding. Anovulatory bleeding triggered by a sudden drop in estrogen levels is called withdrawal bleeding.[77] Anovulatory cycles commonly occur before menopause (perimenopause) and in women with polycystic ovary syndrome.[78]

Very little flow (less than 10 ml) is called hypomenorrhea. Regular cycles with intervals of 21 days or fewer are polymenorrhea; frequent but irregular menstruation is known as metrorrhagia. Sudden heavy flows or amounts greater than 80 ml are termed menorrhagia.[79] Heavy menstruation that occurs frequently and irregularly is menometrorrhagia. The term for cycles with intervals exceeding 35 days is oligomenorrhea.[80]Amenorrhea refers to more than three[79] to six[80] months without menses (while not being pregnant) during a woman's reproductive years. The term for painful periods is Dysmenorrhea.

The menstrual cycle can be described by the ovarian or uterine cycle. The ovarian cycle describes changes that occur in the follicles of the ovary whereas the uterine cycle describes changes in the endometrial lining of the uterus. Both cycles can be divided into three phases. The ovarian cycle consists of the follicular phase, ovulation, and the luteal phase, whereas the uterine cycle consists of menstruation, proliferative phase, and secretory phase.[1]

The follicular phase is the first part of the ovarian cycle. During this phase, the ovarian follicles mature and get ready to release an egg.[1] The latter part of this phase overlaps with the proliferative phase of the uterine cycle.

Through the influence of a rise in follicle stimulating hormone (FSH) during the first days of the cycle, a few ovarian follicles are stimulated.[81] These follicles, which were present at birth[81] and have been developing for the better part of a year in a process known as folliculogenesis, compete with each other for dominance. Under the influence of several hormones, all but one of these follicles will stop growing, while one dominant follicle in the ovary will continue to maturity. The follicle that reaches maturity is called a tertiary or Graafian follicle, and it contains the ovum.[81]

Ovulation is the second phase of the ovarian cycle in which a mature egg is released from the ovarian follicles into the oviduct.[82] During the follicular phase, estradiol suppresses release of luteinizing hormone (LH) from the anterior pituitary gland. When the egg has nearly matured, levels of estradiol reach a threshold above which this effect is reversed and estrogen stimulates the production of a large amount of LH. This process, known as the LH surge, starts around day12 of the average cycle and may last 48 hours.[83]

The exact mechanism of these opposite responses of LH levels to estradiol is not well understood.[84] In animals, a gonadotropin-releasing hormone (GnRH) surge has been shown to precede the LH surge, suggesting that estrogen's main effect is on the hypothalamus, which controls GnRH secretion.[84] This may be enabled by the presence of two different estrogen receptors in the hypothalamus: estrogen receptor alpha, which is responsible for the negative feedback estradiol-LH loop, and estrogen receptor beta, which is responsible for the positive estradiol-LH relationship.[85] However, in humans it has been shown that high levels of estradiol can provoke 32 increases in LH, even when GnRH levels and pulse frequencies are held constant,[84] suggesting that estrogen acts directly on the pituitary to provoke the LH surge.

The release of LH matures the egg and weakens the wall of the follicle in the ovary, causing the fully developed follicle to release its secondary oocyte.[81] If it is fertilized by a sperm, the secondary oocyte promptly matures into an ootid and then becomes a mature ovum. If it is not fertilized by a sperm, the secondary oocyte will degenerate. The mature ovum has a diameter of about 0.2mm.[86]

Which of the two ovariesleft or rightovulates appears essentially random; no known left and right co-ordination exists.[87] Occasionally, both ovaries will release an egg;[87] if both eggs are fertilized, the result is fraternal twins.[88]

After being released from the ovary, the egg is swept into the fallopian tube by the fimbria, which is a fringe of tissue at the end of each fallopian tube. After about a day, an unfertilized egg will disintegrate or dissolve in the fallopian tube.[81]

Fertilization by a spermatozoon, when it occurs, usually takes place in the ampulla, the widest section of the fallopian tubes. A fertilized egg immediately begins the process of embryogenesis, or development. The developing embryo takes about three days to reach the uterus and another three days to implant into the endometrium.[81] It has usually reached the blastocyst stage at the time of implantation.

In some women, ovulation features a characteristic pain called mittelschmerz (German term meaning middle pain).[89] The sudden change in hormones at the time of ovulation sometimes also causes light mid-cycle blood flow.[90]

The luteal phase is the final phase of the ovarian cycle and it corresponds to the secretory phase of the uterine cycle. During the luteal phase, the pituitary hormones FSH and LH cause the remaining parts of the dominant follicle to transform into the corpus luteum, which produces progesterone. The increased progesterone in the adrenals starts to induce the production of estrogen. The hormones produced by the corpus luteum also suppress production of the FSH and LH that the corpus luteum needs to maintain itself. Consequently, the level of FSH and LH fall quickly over time, and the corpus luteum subsequently atrophies.[81] Falling levels of progesterone trigger menstruation and the beginning of the next cycle. From the time of ovulation until progesterone withdrawal has caused menstruation to begin, the process typically takes about two weeks, with 14 days considered normal. For an individual woman, the follicular phase often varies in length from cycle to cycle; by contrast, the length of her luteal phase will be fairly consistent from cycle to cycle.[91]

The loss of the corpus luteum is prevented by fertilization of the egg. The syncytiotrophoblast, which is the outer layer of the resulting embryo-containing structure (the blastocyst) and later also becomes the outer layer of the placenta, produces human chorionic gonadotropin (hCG), which is very similar to LH and which preserves the corpus luteum. The corpus luteum can then continue to secrete progesterone to maintain the new pregnancy. Most pregnancy tests look for the presence of hCG.[81]

The uterine cycle has three phases: menses, proliferative, secretory.[92]

Menstruation (also called menstrual bleeding, menses, catamenia or a period) is the first phase of the uterine cycle. The flow of menses normally serves as a sign that a woman has not become pregnant. (However, this cannot be taken as certainty, as a number of factors can cause bleeding during pregnancy; some factors are specific to early pregnancy, and some can cause heavy flow.)[93][94][95]

Eumenorrhea denotes normal, regular menstruation that lasts for a few days (usually 3 to 5 days, but anywhere from 2 to 7 days is considered normal).[89][96] The average blood loss during menstruation is 35 milliliters with 1080 ml considered normal.[97] Women who experience Menorrhagia are more susceptible to iron deficiency than the average person.[98] An enzyme called plasmin inhibits clotting in the menstrual fluid.[99]

Painful cramping in the abdomen, back, or upper thighs is common during the first few days of menstruation. Severe uterine pain during menstruation is known as dysmenorrhea, and it is most common among adolescents and younger women (affecting about 67.2% of adolescent females).[100] When menstruation begins, symptoms of premenstrual syndrome (PMS) such as breast tenderness and irritability generally decrease.[89] Many sanitary products are marketed to women for use during their menstruation.

The proliferative phase is the second phase of the uterine cycle when estrogen causes the lining of the uterus to grow, or proliferate, during this time.[81] As they mature, the ovarian follicles secrete increasing amounts of estradiol, and estrogen. The estrogens initiate the formation of a new layer of endometrium in the uterus, histologically identified as the proliferative endometrium. The estrogen also stimulates crypts in the cervix to produce fertile cervical mucus, which may be noticed by women practicing fertility awareness.[101]

The secretory phase is the final phase of the uterine cycle and it corresponds to the luteal phase of the ovarian cycle. During the secretory phase, the corpus luteum produces progesterone, which plays a vital role in making the endometrium receptive to implantation of the blastocyst and supportive of the early pregnancy, by increasing blood flow and uterine secretions and reducing the contractility of the smooth muscle in the uterus;[102] it also has the side effect of raising the woman's basal body temperature.[103]

While some forms of birth control do not affect the menstrual cycle, hormonal contraceptives work by disrupting it. Progestogen negative feedback decreases the pulse frequency of gonadotropin-releasing hormone (GnRH) release by the hypothalamus, which decreases the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) by the anterior pituitary. Decreased levels of FSH inhibit follicular development, preventing an increase in estradiol levels. Progestogen negative feedback and the lack of estrogen positive feedback on LH release prevent a mid-cycle LH surge. Inhibition of follicular development and the absence of a LH surge prevent ovulation.[104][105][106]

The degree of ovulation suppression in progestogen-only contraceptives depends on the progestogen activity and dose. Low dose progestogen-only contraceptivestraditional progestogen only pills, subdermal implants Norplant and Jadelle, and intrauterine system Mirenainhibit ovulation in about 50% of cycles and rely mainly on other effects, such as thickening of cervical mucus, for their contraceptive effectiveness.[107] Intermediate dose progestogen-only contraceptivesthe progestogen-only pill Cerazette and the subdermal implant Nexplanonallow some follicular development but more consistently inhibit ovulation in 9799% of cycles. The same cervical mucus changes occur as with very low-dose progestogens. High-dose, progestogen-only contraceptivesthe injectables Depo-Provera and Noristeratcompletely inhibit follicular development and ovulation.[107]

Combined hormonal contraceptives include both an estrogen and a progestogen. Estrogen negative feedback on the anterior pituitary greatly decreases the release of FSH, which makes combined hormonal contraceptives more effective at inhibiting follicular development and preventing ovulation. Estrogen also reduces the incidence of irregular breakthrough bleeding.[104][105][106] Several combined hormonal contraceptivesthe pill, NuvaRing, and the contraceptive patchare usually used in a way that causes regular withdrawal bleeding. In a normal cycle, menstruation occurs when estrogen and progesterone levels drop rapidly.[103] Temporarily discontinuing use of combined hormonal contraceptives (a placebo week, not using patch or ring for a week) has a similar effect of causing the uterine lining to shed. If withdrawal bleeding is not desired, combined hormonal contraceptives may be taken continuously, although this increases the risk of breakthrough bleeding.

Breastfeeding causes negative feedback to occur on pulse secretion of gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH). Depending on the strength of the negative feedback, breastfeeding women may experience complete suppression of follicular development, but no ovulation, or normal menstrual cycle may resume.[108] Suppression of ovulation is more likely when suckling occurs more frequently.[109] The production of prolactin in response to suckling is important to maintaining lactational amenorrhea.[110] On average, women who are fully breastfeeding whose infants suckle frequently experience a return of menstruation at fourteen and a half months postpartum. There is a wide range of response among individual breastfeeding women, however, with some experiencing return of menstruation at two months and others remaining amenorrheic for up to 42 months postpartum.[111]

The word "menstruation" is etymologically related to "moon". The terms "menstruation" and "menses" are derived from the Latin mensis (month), which in turn relates to the Greek mene (moon) and to the roots of the English words month and moon.[112]

Even though the average length of the human menstrual cycle is similar to that of the lunar cycle, in modern humans there is no relation between the two.[113] The relationship is believed to be a coincidence.[114][115] Light exposure does not appear to affect the menstrual cycle in humans.[11] A meta-analysis of studies from 1996 showed no correlation between the human menstrual cycle and the lunar cycle[116], nor did data analysed by period-tracking app Clue, submitted by 1.5m women, of 7.5m menstrual cycles[117].

Dogon villagers did not have electric lighting and spent most nights outdoors, talking and sleeping, so they were apparently an ideal population for detecting a lunar influence; none was found.[118]

In a number of countries, mainly in Asia, legislation or corporate practice has introduced formal menstrual leave to provide women with either paid or unpaid leave of absence from their employment while they are menstruating.[119] Countries with policies include Japan, Taiwan, Indonesia, and South Korea.[119] The practice is controversial due to concerns that it bolsters the perception of women as weak, inefficient workers,[119] as well as concerns that it is unfair to men.[120][121]

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Stem cells treatment clinic – Effective stem cell treatment

more than 60 diseases can be treated with stem cells Read More...

Patient from Portugal, Diagnosed Multiple Sclerosis, One month after treatment he could walk again Read More...

Swiss Medica participated in neuro rehabilitation conference march 2015Read More...

NEW modern technology - activating autologous stem cells and replacing damaged cells

Here you can read all news about stem cells.

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Patient from Portugal, 44 years old. Diagnosed Multiple Sclerosis.

In December 2012 his condition exacerbated. He started using wheelchairs. His disease progressed. He was not able to walk. He was not able to see. Nine months of usual treatments for MS accompanied by chemotherapy did not help. Then he found Swiss Medica Stem Cell Clinic. Stem celltreatment started immediately. One month later he was able to walk again.

See whole story about J Paul >>>

Patient from Uk, 51 years old. Diagnosed Multiple Sclerosis.

After having a stem cell treatment in Moscow his condition, in his words, got 80% better. Before the life changing treatment he was unable to walk long distances without the NHS support. Now he feels much healthier, has more energy and moves without significant difficulties. He is able to regularly go to the gym, he spends time with his two daughters and lives his life to the fullest.

See whole story about Shaun Lawrence >>>

Holistic medicine considers a person to be a functional unit. The disease symptoms are signs of disruption in the system of the body. By activating the bodys ability of self-regulation we can eliminate this disruption. In Swiss Medica XXI Century S.A. we seek the cause of the disease, and provide a setting: to allow the body to use its own powers of self-healing to overcome the disease.

Our primary task is to make your own cells treat your own body. We use advanced technology to activate dormant cells (adipose mesenchymal stem cells) to differentiate into the cells we need, and then to replace the damaged cells. Symptoms become less prominent and disappear.

Testimonials

What they say about us

It`s unbelievable how our life has changed since we had stem cell treatment it`s been nine months.

Mom is calmer, dad is calmer. Why? Because our son is happy, now.

I am very very happy with all the care that I received and I recommend this treatment to anybody who want to give it a go. Come and have an open mind and meet these wonderful people who will treat you gently and with respect.

Ill always be grateful. Thank you.

Well, the first month went well. I regained my psychophysical energy, especially in the sport I practice, I felt an improvement.

Now I hope, I hope that in the future, and the doctors tell me that it is better, I hope that in the future I'll feel all the better.

It's all been very nice, everybody has been very kind.

I don't think that anyone could fail to be impressed by the level of service and treatments and expertise everyone seems to have here, and, obviously, having medical treatment is not something that people want to have, but at the same time it's been as enjoyable as it could be to do that.

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What are adult stem cells? – StemExpress Donor Center

What are adult stem cells?

Most cells in the adult body are specialized cell types. Specialized cell types are differentiated cells that serve a specific purpose in a particular tissue. For example, red blood cells are specifically designed to carry oxygen through the blood. Red blood cells perform their function for 100-120 days; new red blood cells are being formed daily to make sure the body gets its supply of oxygen. So where do these new red blood cells come from? In a process called hematopoiesis, stem cells located in your bone marrow and blood give rise to the cells in your blood, red and white blood cells. Stem cells are undifferentiated cells that exist in all tissues of the adult body and are capable of developing into specialized cells, not just blood cells but muscle, nerve, liver, etc. They function to replenish dying cells and maintain the overall health of our body.

How can studying adult stem cells help us?

Stem cells can be used to study the development of a specific cell type. More specifically scientist can learn about the genes that influence a stem cell to differentiate into a specific cell type. Why is this important? Understanding the developmental process of a specific cell type can help scientist identify genetic defects or how certain diseases arise. For example, at some point through a cells developmental process it can change and become diseased. What genes were involved in creating these changes? At what point in differentiation did this occur? What if there was a way to fix this gene and prevent the disease? These are just some of the questions scientists are trying to answer.

Stem cells can be used for drug discovery. Scientistsare searching for new drugs that improve stem cell function or alter the progress of a disease by identifying potential therapeutic compounds. For example, mesenchymal stem cells (MSCs) found in the bone marrow give rise to connective tissue such as bone, cartilage, and ligaments. What factors promote one specific cell type over the other? Can synthesizing this factor be used in drug therapy? Finding drugs that can promote bone regrowth could aid in alleviating osteoporosis or promote bone healing.

Stem cells can be used in cell replacement therapy. This treatment uses stem cells to generate healthy tissue that replaces damaged tissue caused by disease, aging or injury. For example, during a heart attack the heart sustains damage to not only the muscle tissue but the blood vessels as well. What if stem cells could be used to restore the function of the heart? Scientists have shown that transplanting healthy human stem cells into animal models with damaged hearts regenerates the heart muscle and blood vessels. Breakthroughs like this could potentially replace cardiac bypass surgery, a surgery that is often necessary to restore the blood flow to damaged area of the heart after a heart attack. Within recent years stem cells have been used in studies that target the treatment of Parkinsons, Alzheimers, spinal cord injury, stroke, severe burns, diabetes, arthritis, and leukemia.

What does StemExpress do with the stem cells isolated from your blood or bone marrow?

Isolating stem cells from donated samples of blood or bone marrow can be a time consuming and arduous process. At StemExpress we have developed the technology to isolate these cells quickly and efficiently. Upon request from scientists, isolated stem cells are sent off to their institution where they can begin their research immediately. Cells from StemExpress have been used in a wide variety of research areas, from inherited genetic disease therapies to cancer research.

As the scope of knowledge regarding stem cells expands so to will the potential for treatments of many debilitating diseases. It is donors like you that allow research like this to advance. Donate today and change the lives of tomorrow.

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What are adult stem cells? - StemExpress Donor Center

Adult Stem Cells // Center for Stem Cells and Regenerative …

Adult stem cells, also called somatic stem cells, are undifferentiated cells that are found in many different tissues throughout the body of nearly all organisms, including humans. Unlike embryonic stem cells, which can become any cell in the body (called pluripotent), adult stem cells, which have been found in a wide range of tissues including skin, heart, brain, liver, and bone marrow are usually restricted to become any type of cell in the tissue or organ that they reside (called multipotent). These adult stem cells, which exist in the tissue for decades, serve to replace cells that are lost in the tissue as needed, such as the growth of new skin every day in humans.

Scientists discovered adult stem cells in bone marrow more than 50 years ago. These blood-forming stem cells have been used in transplants for patients with leukemia and several other diseases for decades. By the 1990s, researchers confirmed that nerve cells in the brain can also be regenerated from endogenous stem cells. It is thought that adult stem cells in a variety of different tissues could lead to treatments for numerous conditions that range from type 1 diabetes (providing insulin-producing cells) to heart attack (repairing cardiac muscle) to neurological disease (regenerating lost neurons in the brain or spinal cord).

Efforts are underway to stimulate these adult stem cells to regenerate missing cells within damaged tissues. This approach will utilize the existing tissue organization and molecules to stimulate and guide the adult stem cells to correctly regenerate only the necessary cell types. Alternatively, the adult stem cells could be isolated from the tissue and grown outside of the body, in cultures. This would allow the cells to be easily manipulated, although they are often relatively rare and difficult to grow in culture.

Because the isolation of adult stem cells does not result in the destruction of human life, research involving adult stem cells does not raise any of the ethical issues associated with research utilizing human embryonic stem cells. Thus, research involving adult stem cells has the potential for therapies that will heal disease and ease suffering, a major focus of Notre Dames stem cell research. Combined with our efforts with induced pluripotent stem (iPS) cells, the Center for Stem Cells and Regenerative Medicine will advance the Universitys mission to ease suffering and heal disease.

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CELL AND GENE THERAPY INNOVATION SUMMIT 2019 – Home

Meaning

The Global Cell and Gene Therapy Market is estimated to be worth between 10 to 40 Billion by 2025

The Annual Cell and Gene Therapy Innovation Summit is the only executive gathering committed to creating an advanced networking platform to increase innovation and collaboration within the Cell & Gene Therapy area. Our cutting-edge programme covers critical subjects such as progress cell gene therapy manufacturing, ATMP development, scale-up and scale-out, manufacturing data, R&D, CAR-T therapies, global regulatory affairs, stem cells, cord blood, pricing & reimbursement, improving cost efficiency, commercialization, as well how to leverage innovation to convert cutting-edge research to advance cell gene therapy manufacturing.

Jean-Pierre Latere - COO - Celyad SA

Ohad Karnieli- CEO - ATVIO Biotech Ltd.

Namir Hassan - CSO - Zelluna Immunotherapy

Ajan Reginald - CEO - Celixir

Marina Feschenko- PS-Biogen

David Sourdive-EVP-Cellectics

Katherine Seidl-Director, Oncology - Bluebird Bio

Emanuele Ostuni - Europe Head-Novartis Pharma AG

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CELL AND GENE THERAPY INNOVATION SUMMIT 2019 - Home

Seattle Stem Cell Therapy Clinic | Seattle Sports …

Regenerative Medicine at Seattle Sports & Regenerative Medicine includes the collection and use of therapeutic stem cells to regrow, repair, or replace damaged or diseased tissue within the musculoskeletal system, including: shoulders, elbows, wrists, hips, knees, and ankles.

As your physician, Dr. Wagner is committed to providing the highest level of care, priding himself on staying connected to the ever-changing medical community and the most advanced medical technology available. It is his promise, as your physician, to responsibly provide the most progressive treatments, as long as he is completely confident that they are safe and beneficial for his patients.

Stem cell therapy and Platelet Rich Plasma (PRP) injections are both offered to alleviate pain and repair injury in the bodys tendons and joints, proving to be very effective in such conditions as osteoarthritis, tendon injuries, meniscus and labrum tears. Over 5 million stem cell procedures for osteoarthritis have been performed in the United States with no significant adverse effects reported.

We understand that the use of stem cells may sound complex, however, stem cell therapy is just the opposite. It is a simple procedure, performed in our office during a visit lasting approximately 90 minutes. If you have questions or would like a consultation with Dr. Wagner to learn if you are a candidate for stem cell therapy, please contact Seattle Sports and Regenerative Medicine.

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UAB – School of Medicine – Cell, Developmental and …

Committed to the advancement and pursuit of knowledge, through the achievement of breakthroughs in biomedical research and through the provision of outstanding educational content

The Department of Cell, Developmental and Integrative Biology (CDIB) is a nationally ranked basic science department within the prestigious UAB School of Medicine. In recognition of their research and teaching successes, our outstanding CDIB faculty have earned numerous awards, both locally and nationally. From a financial standpoint, our faculty currently manage in excess of $16M in annual direct costs from extramural funding to support their research programs. Furthermore, our distinguished educators deliver educational content within six schools across UAB and, as a result, have a major impact in countless lives.

CDIB faculty direct five robust and diverse research programs and garner substantial international and national recognition for themselves, as well as our department, and our institution. Faculty research, scientific service, leadership, and scholarly activities reflect our departments vision of uniting exemplary, multidisciplinary academic scholarship, education and research.

CDIB faculty make lasting, noteworthy contributions to the Universitys educational mission both within and beyond the institution. Our educational endeavors range from K-12 and adult educational outreach, to lectures and preceptorships in multiple courses across campus, to leadership roles within the professional and graduate schools.

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UAB - School of Medicine - Cell, Developmental and ...

Gene and Cell Therapy Defined – asgct.org

Gene therapy is a field of biomedical research with the goal of influencing the course of various genetic and acquired (so-called multi factorial) diseases at the DNA/RNA level. Cell therapy aims at targeting various diseases at the cellular level, i.e. by restoring a certain cell population or using cells as carriers of therapeutic cargo. For many diseases, gene and cell therapy are applied in combination. In addition, these two fields have helped provide reagents, concepts, and techniques that are illuminating the finer points of gene regulation, stem cell lineage, cell-cell interactions, feedback loops, amplification loops, regenerative capacity, and remodeling.

Gene therapy is the introduction, removal, or change in the content of a persons genetic code with the goal of treating or curing a disease. Moreover, it is a set of strategies that modify the expression of an individuals genes or repair abnormal genes. Each strategy involves the administration of a specific nucleic acid (DNA or RNA). Nucleic acids are normally not taken up by cells, thus special carriers, so-called 'vectors' are required. Vectors can be of either viral or non-viral nature.

Cell therapy is defined as the administration of living whole cells for the patient for the treatment of a disease. The origin of the cells can be from the same individual (autologous source) or from another individual (allogeneic source). Cells can be derived from stem cells, such as bone marrow or induced pluripotent stem cells (iPSCs), reprogrammed from skin fibroblasts or adipocytes. Stem cells are applied in the context of bone marrow transplantation directly. Other strategies involve the application of more or less mature cells, differentiated in vitro (in a dish) from stem cells.

Historically, the discovery of recombinant DNA technology in the 1970s provided the tools to efficiently develop gene therapy. Scientists used these techniques to readily manipulate bacterial and viral genomes, isolate genes, identify mutations involved in human diseases, characterize and regulate gene expression and produce human proteins from genes (e.g. production of insulin in bacteria revolutionized medicine). Later, various viral and non-viral vectors were developed along with the development of regulatory elements (e.g. promoters that regulate gene expression), which are necessary to induce and control gene expression. Gene transfer in animal models of disease have been attempted and led to early success. Various routes of administrations have been explored (injection into the bloodstream, into the ventricles of the brain, into muscle etc).

The development of suitable gene therapy treatments for many genetic diseases and some acquired diseases has encountered many challenges, such as immune response against the vector or the inserted gene. Current vectors are considered very safe and recent gene therapy trials documented excellent safety profile of modern gene therapy products. Further development involves uncovering basic scientific knowledge of the affected tissues, cells, and genes, as well as redesigning vectors, formulations, and regulatory cassettes for the genes. While effective long-term treatments for many genetic and inherited diseases are elusive today, some success is being observed in the treatment of several types of immunodeficiency diseases, cancers, and eye disorders.

Historically, blood transfusions were the first type of cell therapy and are now considered routine. Bone marrow transplantation has also become a well-established medical treatment for many diseases, including cancer, immune deficiency and others. Cell therapy is expanding its repertoire of cell types for administration. Cell therapy treatment strategies include: isolation and transfer of specific stem cell populations, induction of mature cells to become pluripotent cells, administration of effector cells and reprogramming of mature cells into iPSCs. Administration of large numbers of effector cells has benefited cancer patients, transplant patients with unresolved infections, and patients with vision problems.

Several diseases benefit most from treatments that combine the technologies of gene and cell therapy. For example, some patients have a severe combined immunodeficiency disease (SCID) but unfortunately, do not have a suitable donor of bone marrow. Scientists have identified that patients with SCID are deficient in adenosine deaminase gene (ADA-SCID), or the common gamma chain located on the X chromosome (X-linked SCID). Several dozen patients have been treated with a combined gene and cell therapy approach. Each individuals hematopoietic stem cells were treated with a viral vector that expressed a copy of the relevant normal gene. After selection and expansion, these corrected stem cells were returned to the patients. Many patients improved and required less exogenous enzymes. However, some serious adverse events did occur and their incidence is prompting development of theoretically safer vectors and protocols. The combined approach also is pursued in several cancer therapies.

Genome editing (gene editing) has recently gained significant attention, due to the discovery and application of the clustered regularly interspaced short palindromic repeats (CRISPR) system. Actually, genome editing dates back several years and earlier generation genome editing systems are currently tested in clinical trials (such as zinc-finger nucleases). The aim of genome editing is to disrupt a disease-causing mutation or correct faulty genes at the chromosomal DNA. Genome editing can be performed in the patients own cells in vitro and edited cells can be administered to the patient (thus genome editing can be combined with cell therapy). However, it is also possible to perform genome editing in vivo by administering the genome editing agent packaged in viral and non-viral vectors.

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Stem Cells – The Hastings Center

By Insoo Hyun

Stem cells are undifferentiated cells that have the capacity to renew themselves and to specialize into various cell types, such as blood, muscle, and nerve cells. Embryonic stem cells, derived from five-day-old embryos, eventually give rise to all the different cells and organ systems of the embryo. Embryonic stem cells are pluripotent, because they are capable of differentiating along each of the three germ layers of cells in the embryo, as well as producing the germ line (sperm and eggs). The three germ layers are the ectoderm (skin, nerves, brain), the mesoderm (bone, muscle), and the endoderm (lungs, digestive system).

During later stages of human development, minute quantities of more mature stem cells can be found in most tissue and organ systems, such as bone marrow, the skin, and the gut. These are somatic stem cells, responsible for renewing and repairing the bodys specialized cells. Although the lay public often refers to them as adult stem cells, researchers prefer to call them multipotent because they are less versatile than pluripotent stem cells, and because they are present from the fetal stage of development and beyond. Multipotent stem cells can only differentiate into cells related to the tissue or organ systems from which they originated for instance, multipotent blood stem cells in bonemarrow can develop into different types of blood cells, but not into nerve cells or heart cells.

While multipotent stem cell research has been around for nearly 50 years and has led to clinical therapies for leukemia and other blood disorders, the field of human embryonic stem cell research is still relatively new, and basic discoveries have yet to be directly transitioned into clinical treatments. Human embryonic stem cells were first isolated and maintained in culture in 1998 by James Thomson and colleagues at the University of Wisconsin. Since then, more than a thousand different isolateslines of self-renewing embryonic stem cellshave been created and shared by researchers worldwide.

The main ethical and policy issues with stem cells concern the derivation and use of embryonic stem cells for research. A vocal minority of Americans objects to the destruction of embryos that occurs when stem cells are derived. Embryonic stem cell research is especially controversial for those who believe that five-day-old preimplantation human embryos should not be destroyed no matter how valuable the research may be for society.

To bypass this ethical controversy, the Presidents Council on Bioethics recommended in 2005 that alternative sources of pluripotent stem cells be pursued. Some alternatives have been developed, most notably, the induced pluripotent stem (iPS) cells human skin cells and other body cells reprogrammed to behave like embryonic cells. But embryonic stem cell research will remain needed because there are some questions only they have the potential to answer.

Embryonic stem cells are necessary for several aims of scientific and biomedical research. They include addressing fundamental questions in developmental biology, such as how primitive cells differentiate into more specialized cells and how different organ systems first come into being. By increasing our knowledge of human development, embryonic stem cells may also help us better understand the causes of fetal deformations.

Other important applications lie in the areas of disease research and targeted drug development. By deriving and studying embryonic or other pluripotent stem cells that are genetically-matched to diseases such as Parkinsons disease and juvenile diabetes, researchers are able to map out the developmental course of complex medical conditions to understand how, when, and why diseased specialized cells fail to function properly in patients. Such disease-in-a-dish model systems provide researchers with a powerful new way to study genetic diseases. Furthermore, researchers can aggressively test the safety and efficacy of new, targeted drug interventions on tissue cultures of living human cells derived from disease-specific embryonic stem cells. This method of testing can reduce the risks associated with human subjects research.

One possible way of deriving disease-specific stem cells is through a technique called somatic cell nuclear transfer (SCNT), otherwise known as research cloning. By replacing the DNA of an unfertilized egg with the DNA of a cell from a patients body, researchers are able to produce embryonic stem cells that are genetically-matched to the patient and his or her particular disease. SCNT, however, is technically challenging and requires the collection of high-quality human eggs from female research volunteers, who must be asked to undergo physically burdensome procedures to extract eggs.

A much more widespread and simpler technique for creating disease-specific stem cells was pioneered in 2006 by Shinya Yamanaka and colleagues in Kyoto, Japan. They took mouse skin cells and used retroviruses to insert four genes into them to to create iPS cells. In 2007, teams led by Yamanaka, James Thomson, and George Daley each used similar techniques to create human iPS cells. The iPS cell approach is promising because disease-specific stem cells could be created using skin or blood samples from patients and because, unlike SCNT, it does not require the procurement of human eggs for research.

However, despite these advances, scientists do not believe iPS cells can replace human embryonic stem cells in research. For one, embryonic stem cells must be used as controls to assess the behavior and full scientific potential of iPS cells. Furthermore, iPS cells may not be able to answer some important questions about early human development. And safety is a major issue for iPS cell research aimed at clinical applications, since the cell reprogramming process can cause harmful mutations in the stem cells, increasing the risk of cancer. In light of these and other concerns, iPS cells may perhaps prove to be most useful in their potential to expand our overall understanding of stem cell biology, the net effect of which will provide the best hope of discovering new therapies for patients.

Many who oppose embryonic stem cell research believe for religious or other personal reasons that all preimplantation embryos have a moral standing equal to living persons. On the other hand, those who support embryonic stem cell research point out that not all religious traditions grant full moral standing to early-stage human embryos.

According to Jewish, Islamic, Hindu, and Buddhist traditions, as well as many Western Christian views, moral standing arrives much later during the gestation process, with some views maintaining that the fetus must first reach a stage of viability where it would be capable of living outside the womb. Living in a pluralistic society such as ours, supporters argue, means having to tolerate differences in religious and personal convictions over such theoretical matters as when, during development, moral standing first appears.

Other critics of embryonic stem cell research believe that all preimplantation embryos have the potential to become full-fledged human beings and that they should never have this potential destroyed. In response, stem cell supporters argue that it is simply false that all early-stage embryos have the potential for complete human life many fertility clinic embryos are of poor quality and therefore not capable of producing a pregnancy (although they may yield stem cells). Similarly, as many as 75% to 80% of all embryos created through intercourse fail to implant. Furthermore, no embryos have the potential for full human life until they are implanted in a womans uterus, and until this essential step is taken an embryos potential exists only in the most abstract and hypothetical sense.

Despite the controversies, embryonic stem cell research continues to proceed rapidly around the world, with strong public funding in many countries. In the U.S., federal money for embryonic stem cell research is available only for stem cell lines that are on the National Institutes of Health stem cell registry. However, no federal funds may be used to derive human embryonic stem cell lines; NIH funds may only be used to study embryonic stem cells that were derived using other funding sources.

Despite the lack of full federal commitment to funding embryonic stem cell research in the U.S., there are wide-ranging national regulatory standards. The National Academy of Sciences established guidelines in 2005 for the conduct of human embryonic stem cell research. (See Resources.) According to these guidelines, all privately and publicly funded scientists working with embryonic stem cells should have their research proposals approved by local embryonic stem cell research oversight (ESCRO) committees. ESCRO committees are to include basic scientists, physicians, ethicists, legal experts, and community members to look at stem-cell-specific issues relating to the proposed research. These committees are also to work with local ethics review boards to ensure that the donors of embryos and other human materials are treated fairly and have given their voluntary informed consent to stem cell research teams. Although these guidelines are voluntarily, universities and other research centers have widely accepted them.

At the global level, in 2016 the International Society for Stem Cell Research (ISSCR) released a comprehensive set of professional guidelines for human stem cell research, spanning both bench and clinical stem cell research. (See Resources.) Unlike the NAS guidelines, the ISSCR guidelines go beyond American standards, adding, for example, the recommendation that stem cell lines be banked and freely distributed to researchers around the world to facilitate the fields progress on just and reasonable terms.The potential for over-commercialization and restrictive patenting practices is a major problem facing the stem cell field today, which may delay or reduce the broad public benefit of stem cell research. The promise of broad public benefit is one of thejustifying conditions for conducting stem cell research; without the real and substantial possibility for public benefit, stem cell research loses one of its most important moral foundations.

However, providing useful stem-cell-based therapies in the future is not a simple proposition, either. Developing a roadmap to bring stem cell research into the clinic will involve many complex steps, which the new ISSCR guidelines help address. They include:

These and other difficult issues must be sorted out if stem cell research in all its forms is to fulfill its promise.

STEM CELL GLOSSARY

Newer ethical issues in stem cell research go far beyond the embryo debate, since they encompass all stem cell types, not just human embryonic stem cells, and because they involve human subjects who, despite what one may think about the moral status of preimplantation embryos, are unequivocally moral persons. No other emerging issue better encapsulates the above concern than the growing phenomenon of stem cell tourism. At present, stem cell-based therapies are the clinical standard of care for only afew conditions, such as hematopoietic stem cell transplants for leukemia and epithelial stem cell-based treatments for burns and corneal disorders. Unfortunately, some unscrupulous clinicians around the world are exploiting patients hopes by purporting to provide for large sums of money effective stem cell therapies for many other conditions. These so-called stem cell clinics advance claims about their proffered stem cell therapies without credible scientific rationale, transparency, oversight, or patient protections.

The administration of unproven stem cell interventions outside of carefully regulated research protocols endangers patients and jeopardizes the legitimate progress of translational stem cell scientific research. Patients who travel for unproven stem cell therapies put themselves at risk of physical and financial harm.

The ISSCR guidelines are a good point for thinking about this important problem. The guidelines allow for exceptional circumstances in which clinicians might attempt medically innovative care in a very small number of seriously ill patients, subject to stringent oversight criteria. These criteria include: independent peer review of the proposed innovative procedure and its scientific rationale; institutional accountability; rigorous informed consent and close patient monitoring; transparency; timely adverse event reporting; and a commitment by clinician-scientists to move to a formal clinical trial in a timely manner after experience with at most a few patients. By juxtaposing some current stem cell clinics against the standards outlined in the ISSCR guidelines, one may easily identify some clinics shortcomings and call into question the legitimacy of their purported claims of providing innovative care to patients.

Moving beyond past debates about embryo status to issues concerning the uses of all varieties of stem cells, one can begin to focus the bioethical discourse on areas that have a much broader consensus base of shared values, such as patient and research subject protections and justice. Justice may also call on regulatory and oversight bodies to include a greater involvement of community and patient advocates in the oversight of research. Dealing with the bioethics of stem cell research demands that we wrestle with these and other tough questions.

Insoo Hyun, PhD, is an associate professor of bioethics at Case Western Reserve University.

Read more:
Stem Cells - The Hastings Center