By RENEE WEBB rwebb@catholicglobe.org

As the use of stem cell research and therapy continues to expand, one medical research institute located in Iowa strives to uphold Catholic teachings in bioethics.

The John Paul II Medical Research Institute (JP2MRI), a non-profit of Iowa City, was founded by Dr. Alan Moy in 2007 to address a shortcoming when it came to pro-life values being upheld concerning a variety of medical practices and issues. The doctor also is co-founder and CEO of Cellular Engineering Technologies (CET), a for-profit biotechnology company that manufactures commercial adult stem cells and other biotechnology products.

He explained that JP2MRI was founded a year after starting CET to advance the application of adult stem technology to clinical applications in the area of neurodegenerative disease, rare disease, cancer and chronic diseases of unmet needs or in underperformed diseased areas. His concern was that the United States was falling behind other countries in the area of adult stem cell research.

Recently, through collaborative research by JP2MRI and CET, a new method for creating safer induced pluripotent stem cells, or iPSC, for clinical use was discovered.

We started work in traditional adult stem cells over a decade ago, Moy explained. The controversy was that among the secular scientific community, adult stem cells were viewed as inferior to embryonic stem cells because they could not convert or differentiate into the variety of cells that embryonic stem cells could.

When iPSC technology was discovered by a Japanese Nobel laureate scientist about 10 years ago, it was an ethical alternative to embryonic stem cells. iPSC are noncontroversial adult stem cells that are genetically reprogrammed into embryonic-like stem cells without using human embryos.

But that technology had inherent safety issues just like embryonic stem cells. Most embryonic stem cells and iPS cells have the risk of causing tumors because of their genetic instability, Moy said. What we worked on was trying to reduce the tumor risk.

Building on the original iPSC technology, JP2MRI and CET developed a method by using a variety of chemicals to replace known cancer-causing genes in the process.

Now we have an iPS technology that is safer, said Moy, who noted an added benefit is potential reduced cost in drug development.

Potential applications

He spoke about practical applications of this technology such as expanding the use of stored cord blood stem cells for future medical treatment if a disease develops in the child.

We have a means where we can take the cord blood and make an iPS cell which can have lifelong utility and diversity, Moy added.

For those who do not have stored cord blood, he said all is not lost as blood can be drawn and stored for people to create their own iPS cell for future use.

This technology can also provide a viable alternative to embryonic stem cells and aborted fetal tissue that are currently used by the pharmaceutical industry, noted Moy, to produce vaccines, gene therapy, cell therapy and protein therapeutics.

Right now with protein manufacturing, half of it is done using animal cells to produce human proteins, he explained. The problem is some of the human proteins that are produced have some minor animal characteristics and they are not entirely human so there is a push to produce purely human proteins out of human cells. Unfortunately, the vast majority of human cell lines used in protein manufacturing or in vaccine development are derived from aborted fetal tissue.

Moy anticipates there will increasingly be a movement to shift toward human cell manufacturing, and if we dont come up with non-controversial human cells, we are going to have a lot of controversial human protein therapeutics, gene therapies and vaccines that will be distributed at hospitals that must be administered by doctors.

Morals and ethics

This can create moral and ethical problems. Catholic hospitals and/or Catholic doctors will be forced to decide if they will use that type of product made with illicit cells.

We have to have alternative products that are equal or better than the products that are currently out there, said Moy.

The Catholic Church, as well as the average person, may not always be aware of the unethical nature of many of these products. Moy said he has been trying to communicate areas of concern to the Catholic community for years.

The evolution of biotechnology over decades has become secularized and the power is in the secularists, he said. Advancement of illicit-cell treatment and therapy is a serious potential threat to the Catholic health care system including Catholic hospitals and Catholics who are healthcare providers.

Moy feels strongly about Catholics and the church being pro-active in the bioethics arena.

The only way in which we can influence the biotechnology field is through innovation, he said. Through innovation, if you produce something they want that has technical advantage, then one can influence the direction of biotechnology. Pro-life individuals need to move from a passive bystander to an activist role.

That is part of the reason he founded the JP2MRI, which is grounded in a pro-life bioethics that respects the dignity of every human life. While more than 300 non-profit institutes and organizations engage in and support human embryonic stem cell research, JP2MRI seeks to find cures and therapies exclusively using a variety of adult stem cells and specifically the iPSC, which are derived from adult cells.

Moy said they are not only looking for ways to produce a variety of products using the safer iPS cells, but plan to license them so other scientists, companies and industries can take advantage of these cells to pursue more ethical biotechnology.

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Stem cells: JP2MRI, CET discover safer, more ethical biotechnology - Sioux City Catholic Globe

IPS Cell Therapy Comments Off on Stem cells: JP2MRI, CET discover safer, more ethical biotechnology – Sioux City Catholic Globe | June 30th, 2017

The research studies carried out by John B. Gurdon (Anglo-Saxon) and Shinya Yamanaka (Japanese) were awarded the Nobel Prize in Medicine. These two scientists are considered of being the fathers of cellular reprogramming. They have achieved to create cells that behave identically to embryonic cells, however, without having to destroy human embryos. The Swiss Academy declared that both Gurdon and Yamanaka have revolutionized the current knowledge of how cells and organisms are developed, which has led to the perfection of the absurd methods of diagnosis and therapy.

Jhon Bertrand Gurdon, professor of the Zoology Department of the University of Cambridge, admitted of feeling extremely honored for such a spectacular privilege.

Moreover, Shinya Yamanaka discovered the so called induced pluripotent stem cells (iPS), which have the same proprieties of the embryonic ones and are able to turn into whatever other type of body cell. He asserted that he will continue to conduct research in order to contribute to society and medicine. For him that is a duty.

Yamanaka created four types of genes that supply cells with their pluripotentiality, in other words, the same capacity that embryonic stem cells have. If implanted in differentiated cells, for example of skin, they become pluripotent stem cells. The iPS supply a vast amount of plasticity just as embryonic stem cells do, however, without requiring the extermination or cloning of human embryos, since the initial cells can be obtained from the same patient. In this aspect, these cells have the same status as adult stem cells do, with the advantage of their versatility.

The dilema that has been stirred by the iPS is being resolved due to recent studies carried out by Leisuke Kaji (Universidad de Edimburgo) and Andreas Nagy (Samuel Lunenfeld Research Institute of Mount Sinai Hospital of Toronto).

The created iPS perennially retain their pluripotentiality. There is still the need of research to be conducted concerning the control of the difference between these cells in order for them to create the tissue that is necessary for each case. As Kaji affirms in The Guardian, it is a step towards the practical use of reprogrammed cells in the field of medicine, which could eventually lead to eliminating the need of counting on human embryos as the main source of stem cells.

The Episcopal Subcommittee for the Family and Defense of Life of the Episcopal Conference, beliefs that no Catholic could support practices such as abortion, euthanasia or the production, freezing and/or manipulation of human embryos.

Clement Ferrer

Independent Forum of Opinion

http://indeforum.wordpress.com/

More here:
Hurray for Gurdon and Yamanaka, Nobel Prize Winners for Pro-life Medicine - Gilmer Mirror

IPS Cell Therapy Comments Off on Hurray for Gurdon and Yamanaka, Nobel Prize Winners for Pro-life Medicine – Gilmer Mirror | June 30th, 2017

The research studies carried out by John B. Gurdon (Anglo-Saxon) and Shinya Yamanaka (Japanese) were awarded the Nobel Prize in Medicine. These two scientists are considered of being the fathers of cellular reprogramming. They have achieved to create cells that behave identically to embryonic cells, however, without having to destroy human embryos. The Swiss Academy declared that both Gurdon and Yamanaka have revolutionized the current knowledge of how cells and organisms are developed, which has led to the perfection of the absurd methods of diagnosis and therapy.

Jhon Bertrand Gurdon, professor of the Zoology Department of the University of Cambridge, admitted of feeling extremely honored for such a spectacular privilege.

Moreover, Shinya Yamanaka discovered the so called induced pluripotent stem cells (iPS), which have the same proprieties of the embryonic ones and are able to turn into whatever other type of body cell. He asserted that he will continue to conduct research in order to contribute to society and medicine. For him that is a duty.

Yamanaka created four types of genes that supply cells with their pluripotentiality, in other words, the same capacity that embryonic stem cells have. If implanted in differentiated cells, for example of skin, they become pluripotent stem cells. The iPS supply a vast amount of plasticity just as embryonic stem cells do, however, without requiring the extermination or cloning of human embryos, since the initial cells can be obtained from the same patient. In this aspect, these cells have the same status as adult stem cells do, with the advantage of their versatility.

The dilema that has been stirred by the iPS is being resolved due to recent studies carried out by Leisuke Kaji (Universidad de Edimburgo) and Andreas Nagy (Samuel Lunenfeld Research Institute of Mount Sinai Hospital of Toronto).

The created iPS perennially retain their pluripotentiality. There is still the need of research to be conducted concerning the control of the difference between these cells in order for them to create the tissue that is necessary for each case. As Kaji affirms in The Guardian, it is a step towards the practical use of reprogrammed cells in the field of medicine, which could eventually lead to eliminating the need of counting on human embryos as the main source of stem cells.

The Episcopal Subcommittee for the Family and Defense of Life of the Episcopal Conference, beliefs that no Catholic could support practices such as abortion, euthanasia or the production, freezing and/or manipulation of human embryos.

Clement Ferrer

Independent Forum of Opinion

http://indeforum.wordpress.com/

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The Gilmer Mirror - Hurray for Gurdon and Yamanaka Nobel Prize ... - Gilmer Mirror

IPS Cell Therapy Comments Off on The Gilmer Mirror – Hurray for Gurdon and Yamanaka Nobel Prize … – Gilmer Mirror | June 29th, 2017

Minneapolis, MN, June 26, 2017 (GLOBE NEWSWIRE) -- BioSig Technologies, Inc.(OTCQB:BSGM), a medical device company developing a proprietary platform designed to address an unmet technology need for the $4+ billion electrophysiology (EP) marketplace, today announced that the American Heart Associations 13thAnnualBasic Cardiovascular Sciences (BCVS) 2017 Scientific Sessions: Pathways to Cardiovascular Therapeuticshas accepted two abstracts for presentation that feature novel preclinical findings with BioSigs PURE EP System. The conference will be held July 10-13 in Portland, Oregon and includes the next best thing in cardiovascular research.

The abstracts, entitled, Use of a Novel Electrogram Filter to Visualize the Conduction Tissue Signals in the Ventricle in Sinus Rhythm and Arrhythmia: Canine Studies and "Assessment of Catheter Position Above or Below the Aortic Valve by Evaluation of Characteristics of the Electrogram: An Acute Canine Study", werewritten in collaboration with electrophysiologists from Mayo Clinic and will be presented during scientific poster sessions from 4:30pm 7pm on July 10 and 12, respectively.

BioSig is extremely pleased to have two abstracts, featuring our PURE EP System, accepted into the Basic Cardiovascular Sciences Conference sponsored by the American Heart Association, stated Mr. Ken Londoner, Chief Executive Officer and Chairman of BioSig Technologies. Our collaboration with Mayo Clinic physicians has resulted in seven publications to date featuring BioSigs platform technology. And, we intend to strive towards improving visualization of cardiac signal information during EP procedures to help bring benefits to those patients who suffer with, and doctors who treat, arrhythmia.

About the Basic Cardiovascular Sciences Conference

The 13th Annual BCVS 2017 Scientific Sessions: Pathways to Cardiovascular Therapeutics has become the premier conference for molecular cardiovascular biology and disease. Sponsored by the American Heart Association Basic Cardiovascular Sciences Council, the worlds leading organization of cardiovascular scientists, this conference strives to improve basic cardiovascular regulation through new therapies and insights in cardiovascular disease, as well as research in fields like microRNAs, cardiac gene and cell therapy, cardiac development, as well as tissue engineering and iPS cells.

BCVS 2017 convenes basic and translational cardiovascular scientists from around the world with the common goal to discover pathways to cardiovascular therapeutics and promoting cardiovascular health. This meeting has become the go to meeting for intra- and interdisciplinary cross-fertilization of ideas and incorporation of new approaches from the general scientific community and plays a pivotal role in the training of junior scientists and trainees. The program includes a diversity of speakers representing the best cardiovascular scientists from around the world.

About BioSig Technologies

BioSig Technologies is a medical device company developing a proprietary technology platform designed to improve the $4+ billion electrophysiology (EP) marketplace ( http://www.biosigtech.com). Led by a proven management team and a veteran, independent Board of Directors, Minneapolis-based BioSig Technologies is preparing to commercialize its PURE EP(TM) System. The technology has been developed to address an unmet need in a large and growing market.

The PURE EP System is a novel cardiac signal acquisition and display system which is engineered to assist electrophysiologists in clinical decision making during procedures to diagnose and treat patients with abnormal heart rates and rhythms. BioSigs main goal is to deliver technology to improve upon catheter ablation treatments for prevalent and deadly arrhythmias. BioSig has partnered with Minnetronix on technology development and is working toward FDA 510(k) clearance and CE Mark for the PURE EP System.

Forward-looking Statements

This press release contains forward-looking statements. Such statements may be preceded by the words intends, may, will, plans, expects, anticipates, projects, predicts, estimates, aims, believes, hopes, potential or similar words. Forward-looking statements are not guarantees of future performance, are based on certain assumptions and are subject to various known and unknown risks and uncertainties, many of which are beyond the Companys control, and cannot be predicted or quantified

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Novel Findings Obtained with the PURE EP System to be Presented at American Heart Association's BCVS Scientific ... - Cardiovascular Business

IPS Cell Therapy Comments Off on Novel Findings Obtained with the PURE EP System to be Presented at American Heart Association’s BCVS Scientific … – Cardiovascular Business | June 26th, 2017

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Stem Cell Research is an amazing field right now, and promises to be a powerful and potent tool to help us live longer and healthier lives. Just last month, for example, Stem Cell Therapy was used to restore sight in patients with severe retinal deterioration, allowing them to see clearer than they had in years, or even decades.

Now, there is another form of Stem Cell Treatment on the horizonthis one of a very different form. Stem Cells have now been used as a mechanism to deliver medical treatment designed to eliminate cancer cells, even in hard to reach places. One issue with current cancer treatments is that, treatments that are effective at treating tumors on the surface of the brain cannot be performed safely when the tumor is deeper within the brains tissues.

Stem Cells have the fantastic ability to transform into any other kind of cell within the human body, given the appropriate stimulation. As of today, most of these cells come from Embryonic Lines, but researchers are learning how to backwards engineer cells in the human body, reverting them back to their embryonic state. These cells are known as Induced Pluripotent Stem Cells.

How Does This Stem Cell Cancer Treatment Work?

Using genetic engineering, it is possible to create stem cells that are designed to release a chemical known as Pseudomonas Exotoxin, which has the ability to destroy certain tumor cells in the human brain.

What is Pseudomonas Exotoxin?

Pseudomonas Exotoxin is a compound that is naturally released by a form of bacteria known as Pseudomonas Aeruginosa. This chemical is toxic to brain tumor cells because it prevents polypeptides from growing longer, essentially preventing the polypeptides from growing and reproducing. When used in a specific manner, this toxin has the ability to destroy cancerous and malignant tissue without negatively impacting healthy tissue. In addition to its potential as a cancer treatment, there is also evidence that the therapy could be used for the treatment of Hepatitis B.

PE and Similar Toxins Have been Used Therapeutically in the Past

As of now, this chemical, which we will refer to for the rest of the article as PE, has been used as a cancer treatment before, but there are major limitations regarding the use of PE for particular cancers, not because of the risks of the treatment, but because of the lack of an effective method to deliver the medication to where it is needed.

For example, similar chemicals have been highly effective in the treatment of a large number of blood cancers, but havent been nearly as effective in larger, more inaccessible tumors. The chemicals break down or become metabolized before they can fully do their job.

How do Stem Cells Increase the Effectiveness of PE Cancer Treatment

Right now, PE has to be created in a laboratory before it is administered, which is not very effective for these embedded cancers. By using Stem Cells as an intermediary, it is possible to deliver the medication to deeper areas of the brain more effectively, theoretically highly increasing the efficacy of the treatment.

The leader of this Stem Cell Research is Harvard researcher Dr. Khalis Shah. His goal was to find an effective means to treat these deep brain tumors which are not easily treated by methods available today. In utilizing Stem Cells, Dr. Shah has potentially found a means by which the stem cells can constantly deliver this Cancer Toxin to the tumor area. The cells remain active and are fed by the body, which allows them to provide a steady stream of treatment that is impossible to provide via any other known method.

This research is still in its early stages, and has not yet reached human trials, but in mice, the PE Toxin worked exactly as hypothesized and was able to starve out tumors by preventing them from replicating effectively.

Perhaps this might seem a bit less complicated than it actually is. One of the major hurdles that had to be overcome was that this Toxin would normally be strong enough to kill the cell that hosted it. In order for the Stem Cells to release the cancer, they had to be able to withstand the effects of PE, themselves. Using genetic engineering, Dr. Shah and his associates were able to create a cell that is capable of both producing and withstanding the effects of the toxin.

Stem Cell delivered medical therapy is a 21st century form of medical treatment that researchers are just beginning to learn how to effectively utilize. Essentially, this treatment takes a stem cell and converts it into a unique symbiotic tool capable of feeding off of the host for energy in order to perform a potentially life-saving function. Its really quite fascinating.

How Does PE Not Damage or Kill Brain Cells Indiscriminately?

You might be concerned about the idea of a patient having a toxin injected into the brain to cure a disease. It sounds almost like a dangerous, tribal, homeopathic remedy. In reality, the researchers have been able to harness the destructive power of the toxin and re-engineer it so that it directly targets cancer cells while having limited negative effects on healthy, non-cancerous tissue.

The toxin does its damage after it has been absorbed by a cell. By retooling the toxin so that it does not readily absorb into healthy cells, the dangers associated with having such a potentially dangerous toxin in the brain are seriously and significantly mitigated.

Beyond that, Dr. Shah and his associates have been able to take steps to effectively turn off PE while it is inside the host stem cell, and only activates when it has entered the cancerous tissue. Dr. Shah explains that, although this research has only been conducted in animal subjects, there is no known reason why the effectiveness and safety of the treatment would not be applicable to human patients.

In this treatment, surgeons remove as much of the tumor as possible from the brain, and insert the engineered Stem Cells submerged in a sterile gel in the area where the tumor was removed or partially still exists. Researchers found that, when they used this treatment on laboratory rats, they could tell through imaging and analysis that the modified PE toxin effectively killed the cancer cells, and that this cancer treatment effectively lengthened the life of the rat, as compared to control subjects.

Whats the Next Step?

Of course, cancer treatment is far more complex than a single treatment, no matter how effective that treatment may be. Because human cancer treatment is a comprehensive therapy approach, the end goal of this research is to create a form of therapy in which the method used in animal subjects is combined with other existing approaches, increasing and maximizing the effectiveness of the comprehensive treatment.

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A recent change in how well we understand stem cells may make it easier for scientists and researchers to gather stem cells for use in scientific research as well as medical application. A new study was released in the research publication, Cell, which was performed by representatives from the University of California San Francisco.

One of the issues which hinder the use of stem cells as a more widespread treatment or field of research is that researchers and patients have a bottleneck of available healthy stem cell lines which can be used for research. Researchers hope that this new discovery will allow future scientific discoveries and applications in the areas of creating new and healthy tissue for patients with kidney failure or any other form of organ tissue failure. The future of medical therapy lies with Stem Cell Research, but many other forms of treatment, including Hormone Replacement Therapy, are already in practice today.

Researchers have discovered that it is possible to essentially flip a switch in an adult cell, reverting it back to the preliminary state at which cells existed in one of the earliest stages of developmentthe embryonic stem cell. Medical researchers hypothesize that Stem Cell treatments could be used for a variety of medical health issues which plague the world today, including kidney failure, liver disease, and Type-1 and Type-2 Diabetes.

Use of Embryonic Stem Cells Contentious

There is an ethical issue in Stem Cell Research today. Many Pro-Life Advocates are vociferously against the use of Embryonic Stem Cells harvested from procedures such as fertility treatments designed for conception. They believe that the use of embryonic stem cells harvested from donors and couples looking to conceive is unethical.

Using current research, it may be possible to bypass this ethical quandary completely by using adult cells and converting them into embryonic stem cells. Furthermore, because these stem cells are genetic derivatives of the patient from which the adult cells were harvested, this potentially paves the way for patient-specific medical treatments using stem cells.

After adult cells have been converted back into Embryonic Stem Cells, it will be possible to convert them into any possible cell that the patient needs or would benefit from.

Hijacking the Blueprint of the Cell Allows Scientists to Revert Adult Cells to their Earliest State

Researchers have increased the capacity to produce Embryonic Stem Cells by identifying previously unrecognized biochemical processes which tell human cells how to develop. In essence, researchers have discovered how the body blueprints cells, and can change the blueprints so that a new cell is made.

By utilizing these newly recognized pathways, it is possible to create new stem cells more quickly than ever before. One of the researchers explains the implications of this research. Dr. Miguel Ramalho-Santos is an associate professor of obstetrics, medicine, and cancer research at the University of California San Francisco. Dr. Ramalho-Santos is also a member of the Broad Center of Regenerative Medicine and Stem Cell Research.

He explains that these stem cell discoveries have the ability to alter the way that the medical sciences can take advantage of stem cells with regard to both cancer research and regenerative medicine. Dr. Ramalho-Santos was the lead researcher for this study, and the research was largely funded by the Director of the National Institutes of Health New Innovator Award, granted to promising young researchers which are leading highly innovative and promising medical research studies.

Dr. Ramalho-Santos research builds off of earlier research which discovered that it was possible to take adult cells and turn them back into embryonic stem cells. These stem cells dont have any inherent aging processes, and they can be turned into any other kind of tissue. In the process of this conversion, the adult cells lose all of their unique characteristics, leaving them in an ultimately immature and malleable state.

This earlier research was conducted by researchers from UC San Francisco in partnership with Dr. Shinya Yamanaka from Kyoto University and Gladstone Institutes. These entities all gained a piece of the Nobel Prize in Physiology or Medicine from their part in the study.

Pluripotent Stem Cells vs. Embryonic Stem Cells

Thus far, weve described these cells as Embryonic Stem Cells, but in fact, the more accurate term for these cells are Induced Pluripotent Stem Cells (IPS). These cells are biologically and functionally similar to Embryonic Stem Cells, but have a different name because they are sourced from adult cells. The difference between Induced Pluripotent Stem Cells and Embryonic Stem Cells is that Induced Pluripotent Stem Cells do seem to retain some of the characteristics of their previous state, which appears to limit their ability to convert into any other type of cell. This new research identifies new pathways by which it may be possible to increase the number of cells that an individual IPS Cell can turn into, perhaps allowing them to convert into any other kind of human cell.

Induced Pluripotent Stem Cells are not explicitly considered an alternative to Embryonic Stem Cells, but are considered a different approach to produce similar cells. If researchers fully uncover the mechanisms of how to reprogram these cells, it will lower many barriers to stem cell research and the availability of stem cell treatments.

As of today, researchers have figured out how to make these Induced Pluripotent Stem Cells, but the percentage of adult cells which are reverted successfully is quite low, and frequently, these cells still show some aspects of specialization, which limits their use.

How Do Scientists Make Stem Cells From Adult Cells?

There are genes within every cell which have the ability to induce pluripotency, reverting the cell to an earlier stage of specialization. The initial stage of this process is the result of activating Yamanaka Factors, specific genes that initiate this reversion process.

As of today, this process of de-maturation is not completely understood, and researchers realized from the start that the cells they created were not truly identical to Embryonic Stem Cells, because they still showed signs of their former lives, which often prevented them from being successfully reprogrammed.

The new research conducted by Dr. Ramalho-Santos appears to increase our knowledge regarding how these cells work, and how to program them more effectively. Dr. Ramalho-Santos and his team discovered more genes associated with these programming/reprogramming processes, and by manipulating them, they have increased the viability and range of particular stem cells.

It appears that these genetic impulses are constantly at play to maintain the structure and function of a cell, and that by systematically removing these safeguards, it is possible to increase the ability to alter these cells.

This research increases researchers ability to produce these stem cells, by increasing the ability of medical scientists to produce adequate numbers of stem cells, while also increasing the range of potential treatment options by more effectively inducing the total pluripotency which is available in Embryonic Stem Cells. This research may also help scientists treat certain forms of cancer which are the result of malfunctions of these genes.

Introduction

[Note: Many of the medical and scientific terms used in this summary are found in the NCI Dictionary of Genetics Terms. When a linked term is clicked, the definition will appear in a separate window.]

[Note: Many of the genes described in this summary are found in the Online Mendelian Inheritance in Man (OMIM) database. When OMIM appears after a gene name or the name of a condition, click on OMIM for a link to more information.]

The genetics of skin cancer is an extremely broad topic. There are more than 100 types of tumors that are clinically apparent on the skin; many of these are known to have familial components, either in isolation or as part of a syndrome with other features. This is, in part, because the skin itself is a complex organ made up of multiple cell types. Furthermore, many of these cell types can undergo malignant transformation at various points in their differentiation, leading to tumors with distinct histology and dramatically different biological behaviors, such as squamous cell carcinoma (SCC) and basal cell cancer (BCC). These have been called nonmelanoma skin cancers or keratinocytic cancers.

Figure 1 is a simple diagram of normal skin structure. It also indicates the major cell types that are normally found in each compartment. Broadly speaking, there are two large compartmentsthe avascular cellular epidermis and the vascular dermiswith many cell types distributed in a largely acellular matrix.[1]

Figure 1. Schematic representation of normal skin. The relatively avascular epidermis houses basal cell keratinocytes and squamous epithelial keratinocytes, the source cells for BCC and SCC, respectively. Melanocytes are also present in normal skin and serve as the source cell for melanoma. The separation between epidermis and dermis occurs at the basement membrane zone, located just inferior to the basal cell keratinocytes.

The outer layer or epidermis is made primarily of keratinocytes but has several other minor cell populations. The bottom layer is formed of basal keratinocytes abutting the basement membrane. The basement membrane is formed from products of keratinocytes and dermal fibroblasts, such as collagen and laminin, and is an important anatomical and functional structure. As the basal keratinocytes divide and differentiate, they lose contact with the basement membrane and form the spinous cell layer, the granular cell layer, and the keratinized outer layer or stratum corneum.

The true cytologic origin of BCC remains in question. BCC and basal cell keratinocytes share many histologic similarities, as is reflected in the name. Alternatively, the outer root sheath cells of the hair follicle have also been proposed as the cell of origin for BCC.[2] This is suggested by the fact that BCCs occur predominantly on hair-bearing skin. BCCs rarely metastasize but can invade tissue locally or regionally, sometimes following along nerves. A tendency for superficial necrosis has resulted in the name rodent ulcer.[3]

Some debate remains about the origin of SCC; however, these cancers are likely derived from epidermal stem cells associated with the hair follicle.[4] A variety of tissues, such as lung and uterine cervix, can give rise to SCC, and this cancer has somewhat differing behavior depending on its source. Even in cancer derived from the skin, SCC from different anatomic locations can have moderately differing aggressiveness; for example, SCC from glabrous (smooth, hairless) skin has a lower metastatic rate than SCC arising from the vermillion border of the lip or from scars.[3]

Additionally, in the epidermal compartment, melanocytes distribute singly along the basement membrane and can transform into melanoma. Melanocytes are derived from neural crest cells and migrate to the epidermal compartment near the eighth week of gestational age. Langerhans cells, or dendritic cells, are a third cell type in the epidermis and have a primary function of antigen presentation. These cells reside in the skin for an extended time and respond to different stimuli, such as ultraviolet radiation or topical steroids, which cause them to migrate out of the skin.[5]

The dermis is largely composed of an extracellular matrix. Prominent cell types in this compartment are fibroblasts, endothelial cells, and transient immune system cells. When transformed, fibroblasts form fibrosarcomas and endothelial cells form angiosarcomas, Kaposi sarcoma, and other vascular tumors. There are a number of immune cell types that move in and out of the skin to blood vessels and lymphatics; these include mast cells, lymphocytes, mononuclear cells, histiocytes, and granulocytes. These cells can increase in number in inflammatory diseases and can form tumors within the skin. For example, urticaria pigmentosa is a condition that arises from mast cells and is occasionally associated with mast cell leukemia; cutaneous T-cell lymphoma is often confined to the skin throughout its course. Overall, 10% of leukemias and lymphomas have prominent expression in the skin.[6]

Epidermal appendages are also found in the dermal compartment. These are derivatives of the epidermal keratinocytes, such as hair follicles, sweat glands, and the sebaceous glands associated with the hair follicles. These structures are generally formed in the first and second trimesters of fetal development. These can form a large variety of benign or malignant tumors with diverse biological behaviors. Several of these tumors are associated with familial syndromes. Overall, there are dozens of different histological subtypes of these tumors associated with individual components of the adnexal structures.[7]

Finally, the subcutis is a layer that extends below the dermis with varying depth, depending on the anatomic location. This deeper boundary can include muscle, fascia, bone, or cartilage. The subcutis can be affected by inflammatory conditions such as panniculitis and malignancies such as liposarcoma.[8]

These compartments give rise to their own malignancies but are also the region of immediate adjacent spread of localized skin cancers from other compartments. The boundaries of each skin compartment are used to define the staging of skin cancers. For example, an in situ melanoma is confined to the epidermis. Once the cancer crosses the basement membrane into the dermis, it is invasive. Internal malignancies also commonly metastasize to the skin. The dermis and subcutis are the most common locations, but the epidermis can also be involved in conditions such as Pagetoid breast cancer.

The skin has a wide variety of functions. First, the skin is an important barrier preventing extensive water and temperature loss and providing protection against minor abrasions. These functions can be aberrantly regulated in cancer. For example, in the erythroderma associated with advanced cutaneous T-cell lymphoma, alterations in the regulations of body temperature can result in profound heat loss. Second, the skin has important adaptive and innate immunity functions. In adaptive immunity, antigen-presenting cells engender a TH1, TH2, and TH17 response.[9] In innate immunity, the immune system produces numerous peptides with antibacterial and antifungal capacity. Consequently, even small breaks in the skin can lead to infection. The skin-associated lymphoid tissue is one of the largest arms of the immune system. It may also be important in immune surveillance against cancer. Immunosuppression, which occurs during organ transplant, is a significant risk factor for skin cancer. The skin is significant for communication through facial expression and hand movements. Unfortunately, areas of specialized function, such as the area around the eyes and ears, are common places for cancer to occur. Even small cancers in these areas can lead to reconstructive challenges and have significant cosmetic and social ramifications.[1]

While the appearance of any one skin cancer can vary, there are general physical presentations that can be used in screening. BCCs most commonly have a pearly rim (see Figure 3) or can appear somewhat eczematous. They often ulcerate (see Figure 3). SCCs frequently have a thick keratin top layer (see Figure 4). Both BCCs and SCCs are associated with a history of sun-damaged skin. Melanomas are characterized by asymmetry, border irregularity, color variation, a diameter of more than 6 mm, and evolution (ABCDE criteria). (Refer to What Does Melanoma Look Like? on NCIs website for more information about the ABCDE criteria.) Photographs representing typical clinical presentations of these cancers are shown below.

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Figure 2. Superficial basal cell carcinoma (left panel) and nodular basal cell carcinoma (right panel).

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Figure 3. Ulcerated basal cell carcinoma (left panel) and ulcerated basal cell carcinoma with characteristic pearly rim (right panel).

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Figure 4. Squamous cell carcinoma on the face with thick keratin top layer (left panel) and squamous cell carcinoma on the leg (right panel).

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Figure 5. Melanomas with characteristic asymmetry, border irregularity, color variation, and large diameter.

Basal cell carcinoma (BCC) is the most common malignancy in people of European descent, with an associated lifetime risk of 30%.[1] While exposure to ultraviolet (UV) radiation is the risk factor most closely linked to the development of BCC, other environmental factors (such as ionizing radiation, chronic arsenic ingestion, and immunosuppression) and genetic factors (such as family history, skin type, and genetic syndromes) also potentially contribute to carcinogenesis. In contrast to melanoma, metastatic spread of BCC is very rare and typically arises from large tumors that have evaded medical treatment for extended periods of time. BCCs can invade tissue locally or regionally, sometimes following along nerves. A tendency for superficial necrosis has resulted in the name rodent ulcer. With early detection, the prognosis for BCC is excellent.

Sun exposure is the major known environmental factor associated with the development of skin cancer of all types. There are different patterns of sun exposure associated with each major type of skin cancer (BCC, squamous cell carcinoma [SCC], and melanoma).

While there is no standard measure, sun exposure can be generally classified as intermittent or chronic, and the effects may be considered acute or cumulative. Intermittent sun exposure is obtained sporadically, usually during recreational activities, and particularly by indoor workers who have only weekends or vacations to be outdoors and whose skin has not adapted to the sun. Chronic sun exposure is incurred by consistent, repetitive sun exposure, during outdoor work or recreation. Acute sun exposure is obtained over a short time period on skin that has not adapted to the sun. Depending on the time of day and a persons skin type, acute sun exposure may result in sunburn. In epidemiology studies, sunburn is usually defined as burn with pain and/or blistering that lasts for 2 or more days. Cumulative sun exposure is the additive amount of sun exposure that one receives over a lifetime. Cumulative sun exposure may reflect the additive effects of intermittent sun exposure, chronic sun exposure, or both.

Specific patterns of sun exposure appear to lead to different types of skin cancer among susceptible individuals. Intense intermittent recreational sun exposure has been associated with melanoma and BCC,[2,3] while chronic occupational sun exposure has been associated with SCC. Given these data, dermatologists routinely counsel patients to protect their skin from the sun by avoiding mid-day sun exposure, seeking shade, and wearing sun-protective clothing, although evidence-based data for these practices are lacking. The data regarding skin cancer risk reduction by regular sunscreen use are variable. One randomized trial of sunscreen efficacy demonstrated statistically significant protection for the development of SCC but no protection for BCC,[4] while another randomized study demonstrated a trend for reduction in multiple occurrences of BCC among sunscreen users [5] but no significant reduction in BCC or SCC incidence.[6]

Level of evidence (sun-protective clothing, avoidance of sun exposure): 4aii

Level of evidence (sunscreen): 1aii

Tanning bed use has also been associated with an increased risk of BCC. A study of 376 individuals with BCC and 390 control subjects found a 69% increased risk of BCC in individuals who had ever used indoor tanning.[7] The risk of BCC was more pronounced in females and individuals with higher use of indoor tanning.[8]

Environmental factors other than sun exposure may also contribute to the formation of BCC and SCC. Petroleum byproducts (e.g., asphalt, tar, soot, paraffin, and pitch), organophosphate compounds, and arsenic are all occupational exposures associated with cutaneous nonmelanoma cancers.[9-11]

Arsenic exposure may occur through contact with contaminated food, water, or air. While arsenic is ubiquitous in the environment, its ambient concentration in both food and water may be increased near smelting, mining, or coal-burning establishments. Arsenic levels in the U.S. municipal water supply are tightly regulated; however, control is lacking for potable water obtained through private wells. As it percolates through rock formations with naturally occurring arsenic, well water may acquire hazardous concentrations of this material. In many parts of the world, wells providing drinking water are contaminated by high levels of arsenic in the ground water. The populations in Bangladesh, Taiwan, and many other locations have high levels of skin cancer associated with elevated levels of arsenic in the drinking water.[12-16] Medicinal arsenical solutions (e.g., Fowlers solution and Bells asthma medication) were once used to treat common chronic conditions such as psoriasis, syphilis, and asthma, resulting in associated late-onset cutaneous malignancies.[17,18] Current potential iatrogenic sources of arsenic exposure include poorly regulated Chinese traditional/herbal medications and intravenous arsenic trioxide utilized to induce remission in acute promyelocytic leukemia.[19,20]

Aerosolized particulate matter produced by combustion of arsenic-containing materials is another source of environmental exposure. Arsenic-rich coal, animal dung from arsenic-rich regions, and chromated copper arsenatetreated wood produce airborne arsenical particles when burned.[21-23] Burning of these products in enclosed unventilated settings (such as for heat generation) is particularly hazardous.[24]

Clinically, arsenic-induced skin cancers are characterized by multiple recurring SCCs and BCCs occurring in areas of the skin that are usually protected from the sun. A range of cutaneous findings are associated with chronic or severe arsenic exposure, including pigmentary variation (poikiloderma of the skin) and Bowen disease (SCC in situ).[25]

However, the effect of arsenic on skin cancer risk may be more complex than previously thought. Evidence from in vivo models indicate that arsenic, alone or in combination with itraconazole, can inhibit the hedgehog pathway in cells with wild-type or mutated Smoothened by binding to GLI2 proteins; in this way, these drugs demonstrated inhibition of BCC growth in these animal models.[26,27] Additionally, the effect of arsenic on skin cancer risk may be modified by certain variants in nucleotide excision repair genes (xeroderma pigmentosum [XP] types A and D).[28]

The high-risk phenotype consists of individuals with the following physical characteristics:

Specifically, people with more highly pigmented skin demonstrate lower incidence of BCC than do people with lighter pigmented skin. Individuals with Fitzpatrick skin types I or II were shown to have a twofold increased risk of BCC in a small case-control study.[29] (Refer to the Pigmentary characteristics section in the Melanoma section of this summary for a more detailed discussion of skin phenotypes based upon pigmentation.) Blond or red hair color was associated with increased risk of BCC in two large cohorts: the Nurses Health Study and the Health Professionals Follow-Up Study.[30]

Immunosuppression also contributes to the formation of nonmelanoma (keratinocyte) skin cancers. Among solid-organ transplant recipients, the risk of SCC is 65 to 250 times higher, and the risk of BCC is 10 times higher than in the general population.[31-33] Nonmelanoma skin cancers in high-risk patients (i.e., solid-organ transplant recipients and chronic lymphocytic leukemia patients) occur at a younger age and are more common, more aggressive, and have a higher risk of recurrence and metastatic spread than nonmelanoma skin cancers in the general population.[34,35] Among patients with an intact immune system, BCCs outnumber SCCs by a 4:1 ratio; in transplant patients, SCCs outnumber BCCs by a 2:1 ratio.

This increased risk has been linked to the level of immunosuppression and UV exposure. As the duration and dosage of immunosuppressive agents increases, so does the risk of cutaneous malignancy; this effect is reversed with decreasing the dosage of, or taking a break from, immunosuppressive agents. Heart transplant recipients, requiring the highest rates of immunosuppression, are at much higher risk of cutaneous malignancy than liver transplant recipients, in whom much lower levels of immunosuppression are needed to avoid rejection.[31,36] The risk appears to be highest in geographic areas of high UV radiation exposure: when comparing Australian and Dutch organ transplant populations, the Australian patients carried a fourfold increased risk of developing SCC and a fivefold increased risk of developing BCC.[37] This speaks to the importance of rigorous sun avoidance among high-risk immunosuppressed individuals.

Individuals with BCCs and/or SCCs report a higher frequency of these cancers in their family members than do controls. The importance of this finding is unclear. Apart from defined genetic disorders with an increased risk of BCC, a positive family history of any skin cancer is a strong predictor of the development of BCC.

A personal history of BCC or SCC is strongly associated with subsequent BCC or SCC. There is an approximate 20% increased risk of a subsequent lesion within the first year after a skin cancer has been diagnosed. The mean age of occurrence for these nonmelanoma skin cancers is the mid-60s.[38-43] In addition, several studies have found that individuals with a history of skin cancer have an increased risk of a subsequent diagnosis of a noncutaneous cancer;[44-47] however, other studies have contradicted this finding.[48-51] In the absence of other risk factors or evidence of a defined cancer susceptibility syndrome, as discussed below, skin cancer patients are encouraged to follow screening recommendations for the general population for sites other than the skin.

Mutations in the gene coding for the transmembrane receptor protein PTCH1, or PTCH, are associated with basal cell nevus syndrome (BCNS) and sporadic cutaneous BCCs. PTCH1, the human homolog of the Drosophila segment polarity gene patched (ptc), is an integral component of the hedgehog signaling pathway, which serves many developmental (appendage development, embryonic segmentation, neural tube differentiation) and regulatory (maintenance of stem cells) roles.

In the resting state, the transmembrane receptor protein PTCH1 acts catalytically to suppress the seven-transmembrane protein Smoothened (Smo), preventing further downstream signal transduction.[52] Stoichiometric binding of the hedgehog ligand to PTCH1 releases inhibition of Smo, with resultant activation of transcription factors (GLI1, GLI2), cell proliferation genes (cyclin D, cyclin E, myc), and regulators of angiogenesis.[53,54] Thus, the balance of PTCH1 (inhibition) and Smo (activation) manages the essential regulatory downstream hedgehog signal transduction pathway. Loss-of-function mutations of PTCH1 or gain-of-function mutations of Smo tip this balance toward constitutive activation, a key event in potential neoplastic transformation.

Demonstration of allelic loss on chromosome 9q22 in both sporadic and familial BCCs suggested the potential presence of an associated tumor suppressor gene.[55,56] Further investigation identified a mutation in PTCH1 that localized to the area of allelic loss.[57] Up to 30% of sporadic BCCs demonstrate PTCH1 mutations.[58] In addition to BCC, medulloblastoma and rhabdomyosarcoma, along with other tumors, have been associated with PTCH1 mutations. All three malignancies are associated with BCNS, and most people with clinical features of BCNS demonstrate PTCH1 mutations, predominantly truncation in type.[59]

Truncating mutations in PTCH2, a homolog of PTCH1 mapping to chromosome 1p32.1-32.3, have been demonstrated in both BCC and medulloblastoma.[60,61] PTCH2 displays 57% homology to PTCH1, differing in the conformation of the hydrophilic region between transmembrane portions 6 and 7, and the absence of C-terminal extension.[62] While the exact role of PTCH2 remains unclear, there is evidence to support its involvement in the hedgehog signaling pathway.[60,63]

BCNS, also known as Gorlin Syndrome, Gorlin-Goltz syndrome, and nevoid basal cell carcinoma syndrome, is an autosomal dominant disorder with an estimated prevalence of 1 in 57,000 individuals.[64] The syndrome is notable for complete penetrance and extremely variable expressivity, as evidenced by evaluation of individuals with identical genotypes but widely varying phenotypes.[59,65] The clinical features of BCNS differ more among families than within families.[66] BCNS is primarily associated with germline mutations in PTCH1, but families with this phenotype have also been associated with alterations in PTCH2 and SUFU.[67-69]

As detailed above, PTCH1 provides both developmental and regulatory guidance; spontaneous or inherited germline mutations of PTCH1 in BCNS may result in a wide spectrum of potentially diagnostic physical findings. The BCNS mutation has been localized to chromosome 9q22.3-q31, with a maximum logarithm of the odd (LOD) score of 3.597 and 6.457 at markers D9S12 and D9S53.[64] The resulting haploinsufficiency of PTCH1 in BCNS has been associated with structural anomalies such as odontogenic keratocysts, with evaluation of the cyst lining revealing heterozygosity for PTCH1.[70] The development of BCC and other BCNS-associated malignancies is thought to arise from the classic two-hit suppressor gene model: baseline heterozygosity secondary to germline PTCH1 mutation as the first hit, with the second hit due to mutagen exposure such as UV or ionizing radiation.[71-75] However, haploinsufficiency or dominant negative isoforms have also been implicated for the inactivation of PTCH1.[76]

The diagnosis of BCNS is typically based upon characteristic clinical and radiologic examination findings. Several sets of clinical diagnostic criteria for BCNS are in use (refer to Table 1 for a comparison of these criteria).[77-80] Although each set of criteria has advantages and disadvantages, none of the sets have a clearly superior balance of sensitivity and specificity for identifying mutation carriers. The BCNS Colloquium Group proposed criteria in 2011 that required 1 major criterion with molecular diagnosis, two major criteria without molecular diagnosis, or one major and two minor criteria without molecular diagnosis.[80] PTCH1 mutations are found in 60% to 85% of patients who meet clinical criteria.[81,82] Most notably, BCNS is associated with the formation of both benign and malignant neoplasms. The strongest benign neoplasm association is with ovarian fibromas, diagnosed in 14% to 24% of females affected by BCNS.[74,78,83] BCNS-associated ovarian fibromas are more likely to be bilateral and calcified than sporadic ovarian fibromas.[84] Ameloblastomas, aggressive tumors of the odontogenic epithelium, have also been proposed as a diagnostic criterion for BCNS, but most groups do not include it at this time.[85]

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Andrew LeClerc knew something was wrong when he heard voices when no one else was around. Some were those of people he knew, others were unfamiliar, but all had the authentic mannerisms of real people, not his imagination. He was in his early twenties, unsure of his direction in life, and had been taking synthetic marijuana to ease stress from past traumas. Disturbed by the voices, he sought help in an emergency room and voluntarily admitted himself to a psychiatric hospital, not realizing he would be kept there for six days. He was diagnosed with psychosis, but had little interaction with a therapist. You mostly sit around with coloring books, he says. It felt like a punishment, when all he wanted was help.

Afterward, he contacted therapists, but many were booked. An online search led him to a research study at Beth Israel Deaconess Medical Center in Boston for people newly diagnosed with psychotic disorders. In January 2014, he entered a two-year study that compared two approaches to psychotherapy to help manage cognitive impairments and other symptoms. He was also prescribed an antipsychotic medication.

Eventually he was diagnosed with schizophrenia. Now, about four years later, at 26, LeClerc is learning to live with the condition. Its hard for a person whos diagnosed with schizophrenia to be told somethings not real when they think its real, he says. He continues to take antipsychotic medications that help control his hallucinations and lives in an apartment below his parents in Middleton, Massachusetts. Hes hoping to start a small business, putting his love of gardening to work as a landscaper.

But more importantly, hes learned to make peace with his mind. He likes to say: I dont hear voices, I hear my own brain. When voices do appear, he recognizes them as a product of an aberrant auditory cortex, and he thinks about engaging his prefrontal cortexthe decision-making part of the brainto help him distinguish fact from fiction. I have tools to pull myself back to the moment, he says.

Not everyone who struggles with schizophrenia is able to find such stability. The illness takes many forms; symptoms may include hallucinations and delusions, lack of motivation, and cognitive problems similar to dementia. It tends to strike in the late teens and early twenties, robbing young people of their mental stability just as theyre entering adulthood, beginning careers, or pursuing a college degree. Some improve, while others experience a long mental decline.

The treatments that we have are useful but not great, says Matcheri Keshavan, Cobb professor of psychiatry at Harvard Medical School (HMS) and the leader of the study that LeClerc participated in. The medications used to treat schizophrenia are decades old, and only ameliorate symptoms. Like other psychiatric illnesses, schizophrenia has suffered from a lack of investment from pharmaceutical companies. Says Keshavan, We need better medications that really address the underlying cause of this illness.

But those causes are still mysterious. What scientists do know is that schizophrenia tends to run in families. About 70 percent to 80 percent of a persons risk of developing the illness, Keshavan says, can be explained by genetic factors. Recently, theres been a surge of effort to capitalize on that fact. Advances in genetics have made it possible to search not only for clues about schizophrenia and other psychiatric illnesses hidden within thousands of human genomesbut also for potential new treatments.

As a result, theres been a renaissance in research on schizophrenia and other psychiatric disorders, and some cautious optimism. Its been possible to make real if still early progress in understanding what genes and molecules influence these illnesses, says Steven McCarroll, Flier associate professor of biomedical science and genetics. At Harvard, the leading force is the Stanley Center for Psychiatric Disease Research at the Broad Institute, which is pouring new funding and resources into amassing data on the genetics of mental illness.

Bringing the power of genomics to psychiatric disease fulfills a long-held goal for the Stanley Centers director, Steven Hyman, professor of stem cell and regenerative biology. An HMS professor of psychiatry before becoming head of the National Institute of Mental Health (NIMH) in 1996, Hyman was frustrated by the sluggish progress on the science of psychiatric disorders, as research on illnesses like cancer, heart disease, and diabetes marched ahead. Schizophrenia in particular is challenging to study because its uniquely human. Scientists can study limited aspects of psychiatric illness in animals if they can measure an observable behavior, such as avoiding social interactions or grooming excessively. But psychosis is a problem of thinking; animals, as far as is known, dont experience it in any way we can measure. Its also challenging because brain tissue is so inaccessible. We were really hampered, Hyman says, and I, frankly, didnt know all that much more when I was at NIMH in the late 1990s than careful observers knew at the turn of the twentieth century.

Steven Hyman, director of the Stanley Center for Psychiatric Disease Research Photograph by Stu Rosner

When he left the position, Hyman was interested in researching psychiatric disease but didnt see a rigorous path to do so; instead, he accepted a position as Harvards provosttaking what he now refers to as a 10-year timeout. During that time, a revolution occurred. Genetic technologies and vastly expanded computer power opened new paths for studying the biological basis of complex diseases.

The Broad Institute launched the Stanley Center in 2007 under inaugural director Edward Scolnick, thanks to an initial $100 million in private funding from philanthropists Ted and Vada Stanley, aiming to bring much-needed innovation to treatments for psychiatric disease by harnessing the power of genomics. (The Stanleys provided another $650 million in 2014, an unprecedented gift for psychiatric research.) Partly as a result, the center has gathered the worlds largest collection of DNA samples for studying not only psychiatric diseasesincluding schizophrenia, autism, ADHD, and bipolar disorderbut also healthy control subjects. The resulting data are freely available to the public.

The human genome has started to give us a really powerful way into the problem, Steven McCarroll explains, because the key source of scientific leverage that we have is we know that schizophrenia and other psychiatric illnesses are heritablethey aggregate in families. Their molecular secrets are almost certainly hidden in the way our genomes vary from person to person.

Much of the research on genetics and disease has focused on what McCarroll calls genetic sledgehammersgenes that when mutated would almost certainly make you sick. But schizophrenia, like most common diseases, is genetically complex. The hereditary component of the disease may be a product of tens to hundreds of genetic nudges, variations that dont cause disease by themselves, but together make people vulnerable to illness.

Studying genetic nudges requires amassing large numbers of DNA samples to achieve the statistical power to find subtle variations that may contribute to disease, a project thats taken enormous collaborative effort by many scientists and institutions around the world. The Psychiatric Genomics Consortiumthe largest scientific collaboration involving psychiatric diseaseformed in 2007 and comprises hundreds of investigators in 38 countries and nearly a million genetic samples. The Stanley Center has served as the hub for data sharing, aggregation, and analysis to further the consortiums discoveries.

One of the key tools for uncovering the genetic basis of disease is the genome-wide association study (GWAS)a way of quickly sorting through the common variations in genomes to find those that are more common in people with a given trait or disease than in those without. Associate professor of medicine Mark Daly, who leads the analytic hub of the consortium, says that scientists originally thought such studies might uncover a handful or two of DNA variants that could be statistically correlated with schizophrenia. But rather than identifying a few standouts, the consortiums Schizophrenia Working Group found a crowd of genetic associations, each contributing just a tiny amount of risk. A landmark paper published in 2014 in the journal Nature, led by Michael ODonovan of Cardiff University, described 108 different locations in the genome that harbored variants associated with schizophrenia.

GWAS studies can identify only stretches of DNA: like flags on a zoomed-out map of a city, they provide a neighborhood, not the exact address. We know where the variants are, one of which is likely to be the causal variant, but cant say for sure which one, says assistant professor of medicine Ben Neale, who is developing methods to analyze genomic data. Another approach is to sift through genomes in finer-grained detail by directly reading each letter of the DNA sequence. Such work is time-consuming, but it can help uncover rare genetic differences that are linked to disease, many of which have a stronger effect than common variants. Work by the consortium has also analyzed areas of DNA that are deleted or duplicated, called copy number variations. People with schizophrenia tend to have more such variations overall, and the genes they affect can provide clues to the diseases origins.

Meanwhile, the Stanley Center and other institutions are working to collect thousands more DNA samples from people with schizophrenia and other psychiatric disorders, hoping to identify even more genetic associations of risk. Hyman doesnt see such data-gathering as an endless project. We should kill this problem, he says, meaning in some reasonable number of yearsseven to 10we should have proceeded so far in the genetics of schizophrenia, bipolar disorders, autism, perhaps some other disorders, that weve reached diminishing returns in terms of biological information.

But so far, the picture is still incomplete. The vast majority of genetic samples, for instance, come from people of European ancestry. From a purely scientific point of view, it means were missing a large proportion of the worlds genetic diversity, says Karesten Koenen, professor of psychiatric epidemiology at the Harvard T.H. Chan School of Public Health. Most of that diversity is in Africa: There is much more diversity in African genomes than in those of people from other parts of the world.

Koenen is leading an effort through the Stanley Center to launch genetic research on psychiatric disease in Ethiopia, Uganda, Kenya, and South Africa. Their researchers are partnering with researchers and academic and clinical institutions in those countries and will be gathering DNA samples and clinical information from people diagnosed with schizophrenia. We really want to build local capacity, she says, and develop sustainable research programs that can be led by local scientists and clinicians. The center also plans to extend the effort to Latin America, beginning in Mexico.

This effort will help fill in the genetic picture of psychiatric illness, and will also help correct a vast imbalance. Geneticists are beginning to use data to classify patients based on their risk of developing complex diseases, including schizophrenia. But these risk profiles, Koenen says, lose accuracy when applied to people of African descent. As this kind of profiling makes its way into medicine, she says, Theres a risk that if we dont extend this research to Africa, the health disparity and treatment gap will widen.

What will all this data amount to? Theres a misconception, McCarroll says, that the goal of this research is to conjure up a crystal ball genetic test that will give people personalized treatments based on their unique portfolio of genes. Thats not the aim. Our goal, he says, is to understand the core biological processes in the illnesses, so that innovative treatments can be developed that can treat anyone. Scientists hope that the dizzying array of schizophrenia-related genes will converge onto a few basic processes in the brain, once the function of those genes is understood.

But even as scientists have made dramatic leaps in discovering genetic risk factors of complex diseases, the task of understanding how those genes work is a different, and slower, task.

Researchers from Harvard and the Broad Institute have grown human brain organoids, three-dimensional organ models cultured from stem cells, to study the genetics of psychiatric illness. This series shows (clockwise from upper left) growth at 1, 3, 6, and 9 months, with development of synapses indicated in green. Quadrato et al./Nature 2017

McCarroll was lead author of a study making one of the strongest links between a specific genetic variant and its role in schizophrenia. Working with Aswin Sekar (then a graduate student, now a research fellow), he focused on the most powerful signal of risk in GWAS studies to date, a stretch of DNA in chromosome 6 that was known to harbor many genes involved in the immune system. They focused on one called C4, which has a high degree of variability in humans: each of its different forms may be present in multiple copies in one individual. By using both genetic data and postmortem brain tissue, they found that people with schizophrenia are more likely to have variants of the C4 gene that lead to higher levels of one gene product, C4A, in brain cells.

C4A is one of several proteins involved in a type of immunity called the complement pathway, which helps clear damaged cells and harmful microbes from the body. As part of their study, McCarroll and Sekar collaborated with associate professor of neurology Beth Stevens, whose previous research with mice clarified an ingenious connection between the complement pathway and the brain. Scientists know that as the brain develops, it churns out new cells, which form billions of connections called synapses. In adolescence and early adulthood, some of these connections are pared back, a process called synaptic pruning. In mice, Stevens has found, this pruning is mediated by the complement pathway, which triggers immune cells called microglia to attack neural connections: literally nibbling at synapses.

Sekar, McCarroll, and Stevens also worked with professor of pediatrics Michael Carroll, who had developed mice with varying copies of the C4 gene, and showed that too much C4 activity in the animals can lead to excess pruning. Its too much of a good thing, Stevens says. Their finding suggests that schizophrenia, in some cases, may be caused by loss of synapses in adolescencean especially promising result because it supports clinical observations: synaptic pruning coincides with the age when schizophrenia typically emerges, and brain imaging shows that many people with schizophrenia experience a thinning of the prefrontal cortex in the early stages of disease.

Steven McCarroll, Flier associate professor of biomedical science and genetics Photograph by Stu Rosner

McCarroll emphasizes that the C4A variation contributes only a small amount of risk of disease, but may collude with other variants to tip the brain past a threshold. There are a lot of genetic findings that map to synapses, says Hyman, so some of those other variants may contribute to a larger disruption in how synapses are formed and maintained. But other processes are likely at work in schizophrenia as well. Some genetic risk variants relate to a chemical signal in the brain called glutamate, and others to ion channels, proteins that determine how electrical signals propagate in brain cells. There are also others, Hyman adds, that, frankly, just have us scratching our heads.

The work on C4 offers an example of how genetics is beginning to help neuroscience move forward. Its opened up a ton of new directions and strategies for our group, says Stevens. Across Harvard and the Stanley Center, a growing community is launching collaborative projects with the goal of taking psychiatric disease research into new territories.

One priority is developing new models for teasing out the role of genes in the brain. Scientists have been able to study some behaviors that relate to mental illness in animals, but there is no animal model for schizophrenia. Michael Carroll is now working to extend the C4 study by creating humanized mice that carry human C4 genes, which may make it possible to study their function in a living brain.

Other researchers are trying to develop new ways to study psychiatric disease in humans. Paola Arlotta, professor of stem cell and regenerative biology, explains that when scientists are able to get samples of human brain tissuefrom patients undergoing surgery, postmortem donations, or even tissue from fetusesthe cells die quickly. They cant be propagated and studied in a laboratory, so there is no renewable source of the actual endogenous tissue.

Stem cells have emerged as a way around that problem. Scientists can now take cells from the skin or hair and transform them into induced pluripotent stem (iPS) cells that are capable of becoming other cell types, including brain cells. (At the Stanley Center, Arlotta and other scientists are exploring how to transform iPS cells into specific types of brain cells.) The iPS cells allow scientists to study how cells derived from a person of one genetic background differ from those of another person. Scientists can also use the genome-editing tool CRISPR-Cas9 to introduce specific genetic changes and study their effects.

But theres very little that can be learned about psychiatric disease from isolated cells: brain activity depends on the constant chatter of many cells that are intricately connected. Arlotta has been investigating whether neural stem cells can be spun into something that behaves more like human brain tissue. So-called organoidsclusters of millions of cells up to a few millimeters in diametercan be formed from growing stem cells in a nutrient-rich solution. Organoids have already been used to study events that happen in early development: last year, a team of researchers used them to study the effects of the Zika virus on developing brains.

But since psychiatric diseases like schizophrenia emerge later in life, Arlotta wants to make organoids grow larger and live longer, and to understand whether they can mimic some of the properties of an older brain. This is a new tissue were making, she says, and so the questions that we want to answer are: can we develop them for a very long time, can we understand the cellular composition, can we see if these organoids make actual networks and communicate with each other?

To better characterize these cell-based models, Arlotta and her colleague Kevin Eggan, a fellow professor of stem cell and regenerative biology, are collaborating with McCarroll to apply a technology his lab developedDropSeqthat makes it possible to analyze gene activity in individual cells. The technology will provide a detailed, cell-by-cell understanding of what these models may reveal. In a Nature paper published in April, Arlottas team demonstrated that its possible to cultivate human brain organoids for nine months or more. Analysis revealed that the organoids are filled with a diverse mix of brain-cell types, and that these cells actually form interconnected networks, suggesting they may begin to function in ways that brains do.

But how much meaningful information about psychiatric disorders can be gleaned by studying individual cells or clusters of artificial tissue remains unclear. And an even bigger question is how to use these models to study the effects of genetic nudges. Disease genetics, typically, has been studied by altering or removing genes, one at a time, in an animal. Studying a whole suite of subtle genetic variations in a model system is a completely new idea.

There is no playbook, says Hyman. He acknowledges that the work is risky; many of these projects are possible only because the Stanley Centers open-ended funding makes it easier for labs to work together to pursue new ideas. We spend many tens of millions of dollars a year, and were accountable only at the end of the year to our scientific advisory board, and we tell them our strategy, he says. It gives us enormous flexibility, but its an enormous responsibility.

Some scientists and clinicians believe that gathering genetic data and studying cells is a misguided strategy for alleviating psychiatric illness. They see it as reductionist, and argue that it emphasizes the inborn biological origins of illnesses rather than other factorslike abuse, trauma, drug use, and emotional stressthat are known to play a role in their development. Hyman answers, Genes are not fate, but genes have an awful lot to say. Genetics and the environment both undoubtedly contribute to disease, but both ultimately must act on the brainand genetics happens to be a more tractable way to study whats happening in the brain.

Genetics is already providing insights that could help alter the way psychiatric disorders are defined. People have studied disorders with a box around them, says Elise Robinson, assistant professor of epidemiology, who has analyzed genetic differences within and between disorders such as schizophrenia, bipolar disorder, depression, and autism, which are usually defined by clinical categories outlined in the Diagnostic and Statistical Manual of Mental Disorders. But Robinson says the idea of distinct boundaries separating these disorders is not necessarily consistent with biology. Genetically, psychiatric disorders look more like Venn diagrams with large overlaps. People with schizophrenia share 60 percent to 70 percent of genome-wide variation with those who suffer bipolar disorder, and about 25 percent with autism.

Similarly, there is no simple dividing line between people who have a psychiatric illness and those who dont. Genetic risk for schizophrenia is not something you either have or dont have, she says. Theres a little bit of risk in all of us. Natural variations in many different genes, she explains, have been shown to relate to the way people perform on tests of cognitive or emotional skills. Schizophrenia may emerge from some combination of factors that are part of normal variation in the development and functioning of the human brain. This is true for other complex diseases and many normal traits, she adds: height, for instance, is largely determined by genetics, but theres no single geneor even handful of genesthat controls it. Its a quality that emerges from many genetic inputs.

Robinson believes that scientists could learn more about these disorders by cutting across diagnostic boxes and studying genetic variants that are linked to multiple traits and disorders. Only by understanding how these variants affect the brain can researchers begin to understand how they contribute both to normal brain function and to the risk of disease.

Such research could help demystify the experiences of people like Andrew LeClerc. He has learned to talk about his schizophrenia as something he struggles with, not something that defines him. He describes his condition as a mental difference.

LeClerc also appreciates that not all the voices in his head are negative: he sometimes hears words of encouragement or helpful warnings. As he speaks, his thoughts dont always follow the linear paths of normal conversation, but they can take him into deeper places; he has a keen understanding of how humans brains create their own realities. He sees an analogy to his condition in the once-expensive glass pieces he has begun collecting from his local dump. Glass that seems like trash, he says, can be reused or recycled, so it isnt really broken. He describes himself the same way: Im fragile, not broken.

It may take decades before genetic research on schizophrenia yields new treatments for people like LeClerc, but clues about the biological underpinnings of schizophrenia could help in other ways. Patients with psychiatric disorders get blamed for those disorders in our culture in a way that people with diseases in other organs dont, says McCarroll. If this research can provide a firmer biological understanding of whats happening in the brain, he says, I would hope that we could generate more empathy.

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Probing Psychoses - Harvard Magazine

IPS Cell Therapy Comments Off on Probing Psychoses – Harvard Magazine | June 17th, 2017

When she entered medicine in the mid-1980s, Masayo Takahashi chose ophthalmology as her specialty, she said, because she wanted to have a family and thought the discipline would spare her from sudden work calls in the middle of the night, helping her best balance work and life.

Three decades later, the 55-year-old mother of two grown-up daughters is at the forefront of the nations even the worlds research into regenerative medicine.

In September 2014, she offered a ray of hope to scores of patients suffering from a severe eye condition when her team at the Riken institutes Center for Developmental Biology in Kobe succeeded in a world-first transplanting of cells made from induced pluripotent stem (iPS) cells into a human body.

The operation, conducted as a clinical study, involved creating a retinal sheet from iPS cells, which were developed by Shinya Yamanaka, a researcher at Kyoto University. His 2006 discovery of iPS cells, which can grow into any kind of tissue in the body, won him a Nobel Prize in 2012.

During the 2014 procedure, the retinal sheet was transplanted into a female patient in her 70s with age-related macular degeneration (AMD), an eye disorder that blurs the central field of vision and can lead to blindness. The research team used iPS cells made from the patients own skin cells.

Takahashi made history again in March when she and her team carried out the worlds first transplant of retina cells created from donor iPS cells stocked at Kyoto University. The time and cost necessary for the procedure has been significantly reduced by using the cells, which are made from super-donors, people with special white blood cell types that arent rejected by the immune systems of receiving patients.

Takahashi was in Tokyo last week to speak at the Foreign Press Center and later with The Japan Times. She recounted the highlights of her 25-year research and the numerous legal and other challenges she has overcome.

Takahashi points to the day she led that first iPS transplant surgery Sept. 12, 2014 as the high point of her career so far. Because she worked so hard leading up to the surgery to confirm the safety of the retinal cells, she said that when the operation was over, she was relieved and slept very well.

It wasnt the same for Yamanaka, who provided the stem cells to Takahashi, she said, chuckling. Yamanaka-sensei couldnt sleep well after the surgery because he didnt know about the safety of the cells very well. I should have convinced him.

Some researchers have expressed concern that iPS cell-derived cells have a higher risk of developing cancer. But Takahashi said she knew from the outset that the type her team was making, retinal pigment epithelium (RPE) cells, are extremely unlikely to cause tumors. RPE cells make up the pigmented layer of tissue that supports the light-sensitive cells of the retina.

People in the world think iPS cells are very dangerous because we modify the genes, she said. The retinal pigment epithelium cell is very safe. We knew it from the beginning because we have never seen a metastatic tumor from this cell. Ophthalmologists know very well that this cell is very safe and very good.

The Osaka native said she learned of and became fascinated by the possibility of using stem cells for eye diseases in the mid-1990s, when she took a year off from clinical practice at Kyoto University to work as a researcher at the Salk Institute in San Diego. She moved to Riken in 2006.

More than 2 years have passed since that first iPS surgery, but the transplanted cells remain intact. According to Takahashi, it was not the goal of the research from the outset to improve the eyesight of the patient, who suffered from a very severe case of AMD. Before the surgery, the patient required injections of drugs into her eyeball every two months, but her visual acuity was declining. After the surgery, her acuity stabilized, and more importantly, she is happy, feeling that her vision has brightened and widened, Takahashi said.

Many challenges remain, however, to advance the technology and make it commercially available. One of the issues is cost, Takahashi said, adding that it will take until around 2019 before the cost of the iPS treatment for AMD will fall below 10 million. The first surgery in 2014 cost about 100 million in total, much of which was spent to maintain the clean room and culture the cells.

Still, Takahashi sees a huge potential for iPS cell therapy in her field and beyond.

Every disease has potential to be treated by iPS cell-derived cells or ES (embryonic stem) cell-derived cells in the future, she said, responding to a question on the chances of iPS cells being used to treat ALS, a rare, degenerative neurological disease for which there is currently no cure.

She said she has learned through her experience that some patients are very happy with small improvements.

For ALS, at first, I thought, its a systemic, whole-body disease, so I didnt know how they can fix it, she said. But a doctor (who specializes in ALS) said, its OK, if one finger moves, its (still) OK. So I realized that some benefit will come from cell therapy.

A Matter of Health is a weekly series on the latest health research, technology or policy issues in Japan. It appears on Thursdays.

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Transplants using iPS cells put Riken specialist at forefront of regenerative medicine research - The Japan Times

IPS Cell Therapy Comments Off on Transplants using iPS cells put Riken specialist at forefront of regenerative medicine research – The Japan Times | June 14th, 2017

Scientists have used artificial skin grafts grown from induced pluripotent stem cells to cover the developing spines of rat fetuses while still in the womb.

Asian Scientist Newsroom | June 14, 2017 | In the Lab

AsianScientist (Jun. 14, 2017) - Researchers from Japan have developed a stem cell-based therapy to treat a severe congenital bone defect known as myelomeningocele. Their findings have been published in Stem Cell Reports.

Myelomeningocele is the most serious and common form of spina bifida, a condition in which the backbone and spinal canal do not close before birth, leaving parts of the spinal cord and nerves exposed.

A baby born with this disorder typically has an open area or a fluid-filled sac on the mid to lower back. Most children with this condition are at risk of brain damage because too much fluid builds up in their brains. They also often experience symptoms such as loss of bladder or bowel control, loss of feeling in the legs or feet, and paralysis of the legs.

To develop a minimally invasive treatment to cover large myelomeningocele defects earlier during pregnancy, the researchers first generated artificial skin from human induced pluripotent stem cells (iPSCs), and then successfully transplanted the skin grafts into rat fetuses with the condition.

We provide preclinical proof of concept for a fetal therapy that could improve outcomes and prevent lifelong complications associated with myelomeningoceleone of the most severe birth defects, said senior study author Professor Akihiro Umezawa of Japan's National Research Institute for Child Health and Development.

Since our fetal cell treatment is minimally invasive, it has the potential to become a much-needed novel treatment for myelomeningocele.

The human iPSCs were generated from fetal cells taken from amniotic fluid from two pregnancies with severe fetal disease (Down syndrome and twin-twin transfusion syndrome). The researchers then used a chemical cocktail in a novel protocol to turn the iPSCs into skin cells and treated these cells with additional compounds such as epidermal growth factor to promote their growth into multi-layered skin.

In total, it took approximately 14 weeks from amniotic fluid preparation to 3D skin generation, which would allow for transplantation to be performed in humans during the therapeutic window of 28-29 weeks of gestation.

Next, the researchers transplanted the 3D skin grafts into 20 rat fetuses through a small incision in the uterine wall. The artificial skin partially covered the myelomeningocele defects in eight of the newborn rats and completely covered the defects in four of the newborn rats, protecting the spinal cord from direct exposure to harmful chemicals in the external environment.

Moreover, the engrafted 3D skin regenerated with the growth of the fetus and accelerated skin coverage throughout the pregnancy period. Notably, the transplanted skin cells did not lead to tumor formation, but the treatment significantly decreased birth weight and body length.

We are encouraged by our results and believe that our fetal stem cell therapy has great potential to become a novel treatment for myelomeningocele, Umezawa said. However, additional studies in larger animals are needed to demonstrate that our fetal stem cell therapy safely promotes long-term skin regeneration and neurological improvement.

The article can be found at: Kajiwara et al. (2017) Fetal Therapy Model of Myelomeningocele with Three-dimensional Skin Using Amniotic Fluid Cell-derived Induced Pluripotent Stem Cells.

Source: Cell Press; Photo: Kazuhiro Kajiwara. Disclaimer: This article does not necessarily reflect the views of AsianScientist or its staff.

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3D Artificial Skin Used To Treat Spina Bifida In Rats - Asian Scientist Magazine

IPS Cell Therapy Comments Off on 3D Artificial Skin Used To Treat Spina Bifida In Rats – Asian Scientist Magazine | June 14th, 2017

Tissue-specific stem cells

Tissue-specific stem cells, which are sometimes referred to as adult or somatic stem cells, are already somewhat specialized and can produce some or all of the mature cell types found within the particular tissue or organ in which they reside. Because of their ability to generate multiple, organ-specific, cell types, they are described as multipotent. For example, stem cells found

Stem cells are the foundation cells for every organ and tissue in our bodies. The highly specialized cells that make up these tissues originally came from an initial pool of stem cells formed shortly after fertilization. Throughout our lives, we continue to rely on stem cells to replace injured tissues and cells that are lost every day, such as those in our skin, hair, blood and the lining of our gut. Stem cells have two key properties: 1) the ability to self-renew, dividing in a way that makes copies of themselves, and 2) the ability to differentiate, giving rise to the mature types of cells that make up our organs and tissues.

Tissue-specific stem cells Tissue-specific stem cells, which are sometimes referred to as adult or somatic stem cells, are already somewhat specialized and can produce some or all of the mature cell types found within the particular tissue or organ in which they reside. Because of their ability to generate multiple, organ-specific, cell types, they are described as multipotent. For example, stem cells found within the adult brain are capable of making neurons and two types of glial cells, astrocytes and oligodendrocytes. Tissue-specific stem cells have been found in several organs that need to continuously replenish themselves, such as the blood, skin and gut and have even been found in other, less regenerative, organs such as the brain. These types of stem cells represent a very small population and are often buried deep within a given tissue, making them difficult to identify, isolate and grow in a laboratory setting. Neuron Dr. Gerry Shaw, EnCor Biotechnology Inc. Astrocyte Abcam Inc. Oligodendrocyte Dhaunchak and Nave (2007). Proc Natl Acad Sci USA 104:17813-8 http://www.isscr.org Embryonic stem cells Embryonic stem cells have been derived from a variety of species, including humans, and are described as pluripotent, meaning that they can generate all the different types of cells in the body. Embryonic stem cells can be obtained from the blastocyst, a very early stage of development that consists of a mostly hollow ball of approximately 150-200 cells and is barely visible to the naked eye. At this stage, there are no organs, not even blood, just an inner cell mass from which embryonic stem cells can be obtained. Human embryonic stem cells are derived primarily from blastocysts that were created by in vitro fertilization (IVF) for assisted reproduction but were no longer needed. The fertilized egg and the cells that immediately arise in the first few divisions are totipotent. This means that, under the right conditions, they can generate a viable embryo (including support tissues such as the placenta). Within a matter of days, however, these cells transition to become pluripotent. None of the currently studied embryonic stem cell lines are alone capable of generating a viable embryo (i.e., they are pluripotent, not totipotent). Why are embryonic stem cells so valuable? Unlike tissue-specific (adult) stem cells, embryonic stem cells have the potential to generate every cell type found in the body. Just as importantly, these cells can, under the right conditions, be grown and expanded indefinitely in this unspecialized or undifferentiated state. These cells help researchers learn about early human developmental processes that are otherwise inaccessible, study diseases and establish strategies that could ultimately lead to therapies designed to replace or restore damaged tissues. Induced pluripotent stem cells One of the hottest topics in stem cell research today is the study of induced pluripotent stem cells (iPS cells). These are adult cells (e.g., skin cells) that are engineered, or reprogrammed, to become pluripotent, i.e., behave like an embryonic stem cell. While these iPS cells share many of the same characteristics of embryonic stem cells, including the ability to give rise to all the cell types in the body, it is important to understand that they are not identical. The original iPS cells were produced by using viruses to insert extra copies of three to four genes known to be important in embryonic stem cells into the specialized cell. It is not yet completely understood how these three to four reprogramming genes are able to induce pluripotency; this question is the focus of ongoing research. In addition, recent studies have focused on alternative ways of reprogramming cells using methods that are safer for use in clinical settings. Disease- or patient-specific pluripotent stem cells One of the major advantages of iPS cells, and one of the reasons that researchers are very interested in studying them, is that they are a very good way to make pluripotent stem cell lines that are specific to a disease or even to an individual patient. Disease-specific stem cells are powerful tools for studying the cause of a particular disease and then for testing drugs or discovering other approaches to treat or cure that disease. The development of patientspecific stem cells is also very attractive for cell therapy, as these cell lines are from the patient themselves and may minimize some of the serious complications of rejection and immunosuppression that can occur following transplants from unrelated donors. Moving stem cells into the clinic Clinical translation is the process used to turn scientific knowledge into real world medical treatments. Researchers take what they have learned about how a tissue usually works and what goes wrong in a particular disease or injury and use this information to develop new ways to diagnose, stop or fix what goes wrong. Before being marketed or adopted as standard of care, most treatments are tested through clinical trials. Sometimes, in attempting new surgical techniques or where the disease or condition is rare and does not have a large enough group of people to form a clinical trial, certain treatments might be tried on one or two people, a form of testing sometimes referred to as innovative medicine. For more information on how science becomes medicine, please visit http://www.closerlookatstemcells.org. Current therapies Blood stem cells are currently the most frequently used stem cells for therapy. For more than 50 years, doctors have been using bone marrow transplants to transfer blood stem cells to patients, and more advanced techniques for collecting blood stem cells are now being used to treat leukemia, lymphoma and several inherited blood disorders. Umbilical cord blood, like bone marrow, is often collected as a source of blood stem cells and in certain cases is being used as an alternative to bone marrow transplantation. Additionally, some bone, skin and corneal diseases or injuries can be treated by grafting tissues that are derived from or maintained by stem cells. These therapies have also been shown to be safe and effective. Potential therapies Other stem cell treatments, while promising, are still at very early experimental stages. For example, the mesenchymal stem cell, found throughout the body including in the bone marrow, can be directed to become bone, cartilage, fat and possibly even muscle. In certain experimental models, these cells also have some ability to modify immune functions. These abilities have created considerable interest in developing ways of using mesenchymal stem cells to treat a range of musculoskeletal abnormalities, cardiac disease and some immune abnormalities such as graft-versus-host disease following bone marrow transplant. Remaining challenges Despite the successes we have seen so far, there are several major challenges that must be addressed before stem cells can be used as cell therapies to treat a wider range of diseases. First, we need to identify an abundant source of stem cells. Identifying, isolating and growing the right kind of stem cell, particularly in the case of rare adult stem cells, are painstaking and difficult processes. Pluripotent stem cells, such as embryonic stem cells, can be grown indefinitely in the lab and have the advantage of having the potential to become any cell in the body, but these processes are again very complex and must be tightly controlled. iPS cells, while promising, are also limited by these concerns. In both cases, considerable work remains to be done to ensure that these cells can be isolated and used safely and routinely. Second, as with organ transplants, it is very important to have a close match between the donor tissue and the recipient; the more closely the tissue matches the recipient, the lower the risk of rejection. Being able to avoid the lifelong use of immunosuppressants would also be preferable. The discovery of iPS cells has opened the door to developing patient-specific pluripotent stem cell lines that can later be developed into a needed cell type without the problems of rejection and immunosuppression that occur from transplants from unrelated donors. Third, a system for delivering the cells to the right part of the body must be developed. Once in the right location, the new cells must then be encouraged to integrate and function together with the bodys other cells. http://www.isscr.org Glossary Blastocyst A very early embryo that has the shape of a ball and consists of approximately 150-200 cells. It contains the inner cell mass, from which embryonic stem cells are derived, and an outer layer of cells called the trophoblast that forms the placenta. Cell line Cells that can be maintained and grown in a dish outside of the body. Clinical translation The process of using scientific knowledge to design, develop and apply new ways to diagnose, stop or fix what goes wrong in a particular disease or injury. Differentiation The process of development with an increase in the level of organization or complexity of a cell or tissue, accompanied by a more specialized function. Embryo The early developing organism; this term denotes the period of development between the fertilized egg and the fetal stage. Embryonic stem cell Cells derived from very early in development, usually the inner cell mass of a developing blastocyst. These cells are self-renewing (can replicate themselves) and pluripotent (can form all cell types found in the body). Induced pluripotent stem (iPS) cell Induced pluripotent cells (iPS cells) are stem cells that were engineered (induced) from non-pluripotent cells to become pluripotent. In other words, a cell with a specialized function (for example, a skin cell) that has been reprogrammed to an unspecialized state similar to that of an embryonic stem cell. Innovative medicine Treatments that are performed on a small number of people and are designed to test a novel technique or treat a rare disease. These are done outside of a typical clinical trial framework. In vitro fertilization A procedure in which an egg cell and sperm cells are brought together in a dish to fertilize the egg. The fertilized egg will start dividing and, after several divisions, forms the embryo that can be implanted into the womb of a woman and give rise to pregnancy. Mesenchymal stem cells Mesenchymal stem cells were originally discovered in the bone marrow, but have since been found throughout the body and can give rise to a large number of connective tissue types such as bone, cartilage and fat. Multipotent stem cells Stem cells that can give rise to several different types of specialized cells, but in contrast to a pluripotent stem cell, are restricted to a certain organ or tissue types. For example, blood stem cells are multipotent cells that can produce all the different cell types that make up the blood but not the cells of other organs such as the liver or brain. Pluripotent stem cells Stem cells that can become all the cell types that are found in an implanted embryo, fetus or developed organism. Embryonic stem cells are pluripotent stem cells. Self-renewal The process by which a cell divides to generate another cell that has the same potential. Stem cells Cells that have both the capacity to self-renew (make more stem cells by cell division) and to differentiate into mature, specialized cells. Tissue-specific stem cells (also known as adult or somatic stem cells) Stem cells found in different tissues of the body that can give rise to some or all of the mature cell types found within the particular tissue or organ from which they came, i.e., blood stem cells can give rise to all the cells that make up the blood, but not the cells of organs such as the liver or brain. Totipotent stem cells Stem cells that, under the right conditions, are wholly capable of generating a viable embryo (including the placenta) and, for humans, exist until about four days after fertilization, prior to the blastocyst stage from which embryonic stem cells are derived.

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What Are Stem Cells - Checkbiotech.org (press release)

IPS Cell Therapy Comments Off on What Are Stem Cells – Checkbiotech.org (press release) | June 4th, 2017

Seven drugs of the current top-10 best selling drugs are biologics, the penetration of biologic drugs is expected to reach 30% by 2020 of the global pharmaceutical market and some of the key modalities include monoclonal antibodies, recombinant proteins, peptides, cell and gene therapy products.

Dr Subir Basak Chief Business Officer, GVK Biosciences

Over the last two decades, the Pharmaceutical industry has seen a radical change. The unprecedented downsizing of the internal discovery of big pharmaceuticals, patent expiration, shift towards biologics have seen a surge in the externalization and outsourcing activities. As the industry is looking for new sources of discovery and innovation with limited resources, there is a growing preference to move towards externalization and willingness to embrace the concept of outsourcing.

Seven drugs of the current top- 10 best selling drugs are biologics, the penetration of biologic drugs is expected to reach 30% by 2020 of the global pharmaceutical market and some of the key modalities include monoclonal antibodies, recombinant proteins, peptides, cell and gene therapy products. Global R&D spend in the biopharmaceutical industry is estimated to be $194 billion in 2016 and according to industry experts, 75-80% of the expenses can be outsourced. However, current penetration rate is around 58% which presents a huge opportunity for the CROs to tap the Trends in Drug Discovery Outsourcing: A Perspective market. The global pharmaceutical outsourcing market was estimated to be $113.7 billion in 2016 and out of which 49% is accounted for CROs. Among the $55.7 billion CRO market, 31.2% accounts for discovery-based service i.e. $17.4 billion in 2016 and the remaining 68.8% accounts for Preclinical and clinical services.

Biology related services segment is a high growth area with huge potential and expected to grow faster at a CAGR of 17.2% compared to the small molecules segment due to increase in budget allocations for R&D by biopharmaceutical companies.

The drug discovery CRO industry is witnessing increased consolidation. Many Asia-based companies are increasing their foothold in Europe and North America. GVK BIO, a Contract Research & Development Organization (CRDO) from India has taken over Aragen Bioscience. Aragen has early stage discovery biologics capabilities and played a leading role in oncology and fibrosis based animal models for preclinical biotechs in bay area. Similarly, ChemPartner established research facility in South San Francisco. Also, WuXi AppTec acquired HD Biosciences (HDB), a biology focused preclinical drug discovery CRO.

Advancement in drug discovery technologies such as iPS cells, automated high content screening, patch clamp, gene editing and DNAencoded libraries have expedited the drug discovery process with increased efficiency. There is an increased interest in the use of DNAencoded libraries (small molecules tagged with DNAs) by major pharma companies.Majority of the companies offering DNA-encoded library services are from US (DiCE, X-Chem, Ensemble therapeutics) and Europe (Nuevolution, Vipergen, Cominnex, Philochem). Thereseems to be very little competition in APAC. This trend should push some of the CROs from APAC region to acquire companies with proprietary technology in DNA-encoded libraries or to build capabilities and this seems likely to be a focus point for majority of the CROs especially from APAC.

Evolving business models including risk-based and insourcing are facilitating better collaboration between pharmaceutical companies and CROs. Some of the companies established a new business model known as insourcing which is a new sourcing for pharma where CROs work on-site at customer location in an integrated fashion. This new model provides outstanding performance with efficient cost and time.

CROs should build capabilities to differentiate in the area of Target Identification/Target Validation on how to use human disease pathology knowledge/primary tissues from humans clubbed with Omics knowledge to further validate the concepts. As most of the CROs propose targets from literature and sponsor companies consider it as risky option to invest in such projects without substantial evidences. As a de-risking strategy some CROs are investing internally and validating the concept by siRNA, knockdown approaches and take the concept to a level-up and then approach the sponsors companies who are working in similar area. This approach would increase the sponsor confidence in the CRO program.

There is a huge demand for the novel therapeutics addressing the unmet needs, for example, there are no FDA approved drugs or any therapies for NASH treatment and there is a tremendous opportunity for CROs to work on novel targets, preclinical models and biomarker to come-up with some early stage assets for partnering. Owing to market attractiveness, there is funding provided by venture capitalists to promising players, while some investors are even launching new companies to specifically work on NASH projects. For instance in February 2017, Versant Ventures formed Jecure Therapeutics through $20 million investment for NASH program development. Similarly, Third Rock Ventures formed Pliant Therapeutics with $45 million investment for TGF- signaling based NASH treatment. These companies could potentially outsource majority of the work to CROs in APAC region.

Asia is emerging as a preferred destination for outsourcing drug discovery activities due to the vast availability of skilled manpower, lower costs, favorable regulatory environment and quality data. In addition the local governments are focusing on development of healthcare and pharmaceutical industryby ensuring focus on high quality & compliance in terms of higher regulatory surveillance and training programs. Japan being the second largest pharmaceutical market in the world provides huge opportunity for CROs from APAC. Chinese and Indian pharmaceutical markets are one of the fastest growing in the world and are considered to be the preferred locations for drug discovery outsourcing primarily because of the end-to-end technological capabilities developed over several years. Asian CROs have strong capabilities in biologics research services and built new technology platforms for high-throughput screening, genomics and proteomics research panel screening, enzymatic, and binding assays. They are also well equipped with transgenic and disease animal models that have been developed for target validation, efficacy, and safety studies, thereby providing clients with end-to-end services. Indian CROs typically focus more on new chemical entities and offer integrated discovery services at much lower cost.

Therapeutic area gap analysis research indicates that the key contract research organizations in Asia pacific region are majorly focusing on Oncology, metabolic diseases, Inflammation and CNS. However, majority of Pharma companies in addition to the above therapeutic areas are also focusing on other areas like cardiovascular, immunology, infectious diseases. Since there is a high gap in these therapeutic areas, the CROs should increase their focus in order to tap the opportunity.

Growth in biologics research and orphan drugs, innovative technological platforms and evolving business models encourage pharma and biotech companies to outsource. Even though, big pharma is moving towards research institutions and academia to accelerate knowledge and leverage innovation and technology platforms, they lack the infrastructure to move the drugs from early stages of drug discovery. These factors are expected to enhance drug discovery outsourcing market in APAC region for the coming years.

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Trends in Drug Discovery Outsourcing: A Perspective - BSA bureau (press release)

IPS Cell Therapy Comments Off on Trends in Drug Discovery Outsourcing: A Perspective – BSA bureau (press release) | June 2nd, 2017

BENGALURU:Full-fledged treatment for cancer and bone-related ailments using stem-cell within the state could soon be a possibility if a plan of a world renowned surgeon from the state succeeds.

Dr A A Shetty is a highly decorated orthopedic surgeon and professor based in the UK who won the Nobel equivalent of surgery called the Hunterian Medal, this year. In his aim to bring about next level cancer and orthopedic treatment, he has already set up two big stem cell research labs - one in Dharwad and another in Mangaluru, a few years back at a cost of around 20 to 25 crore. A hospital that will treat stem-related ailments has also been envisaged at a total cost of around Rs 200 to 250 crore.

Setting up the labs is part of a three-step goal. After setting up the labs, the next step will be producing the stem cells, whether it be for bone ailments, treatment for cervical cancer etc. Then the third step will be the application of these stem cells through our hospital or through tie-ups with other hospitals. I have already received the funding for setting up the hospital, says Dr Shetty in an interaction with CE in Bengaluru. He is originally from a small village called Asode in Udupi district.

The lab in Dharwad is located at SDM College and is being backed by Shri Dharmasthala Manjunatheshwara and will be primarily working on blood cancer and thalassemia treatment. The one in Mangaluru is located at K.S. Hegde Medical Academy (KSHEMA) and is backed by the NITTE group. It will work on cartilage and bone fracture treatments.The effort is no doubt for profit. We will charge the rich but the poor will be treated for free at our hospital, he says.

Already, Shetty has recruited a number of top stem cell researchers from the state who are presently abroad. I have recruited researchers who were doing their postdoc studies in Japan, South Korea. Presently there are four of them working at the two labs, he says. Shetty ultimately wants to settle in Karnataka and hopes to achieve his goal by 2020. The third stage of his plan also requires expertise in various cutting edge technologies such as robotics, computing and he will also be recruiting people who specialize in these fields.

Cancer Vaccination

Shetty also hopes to make cancer vaccination a possibility. Giving an example of cervical cancer, Shetty says, Few cancers can be vaccinated. Cervical cancer, one of the most rampant cancers, is one of them. We will use stems derived from iPS cell. In the UK, the vaccine cost 60 pounds. Our aim is to develop it and sell it at a very low cost, as low as Rs 100, he adds. Induced Pluripotent Stem Cells or iPS Cells are derived from the blood and skiwwn cells and can be reprogrammed to provide an unlimited source of any type of human cell.

Stem cells for Arthritis In 2013, Shetty devised a minimally invasive procedure to treat arthritis using stem cells. When the cartilage between the bones begin to erode, the bones rub against each other and cause severe pain. Shetty treated a patient suffering from knee arthritis. He drilled a hole into the patients knee bone and released stem cells that could grow into the cartilage. In all, the procedure lasted just 30 minutes. Shetty has already done as many as two dozen such procedures in India.

Trauma Center Shetty also says that he wants to develop and provide integrated trauma services. If a patient survives the golden hour then he/she can be saved. Majority die in the first hour of trauma. My integrated services will have specialized suits that will help reduce blood loss and will have other know-how. I am negotiating with the International Rotary on this, he adds. This may be established either in Mangalore or Bangalore.

Dr Vishal Rao, head and neck oncology surgeon at HCG Hospitals says that stem cells research is in the mid-stage of development and has great potential to grow in India. The IT and BT ministry is already taking great steps by encouraging startups on these lines, starting various schemes, he says. Vishal also pointed out that a number of private organizations, hospitals and individuals like those like Dr Shetty are also investing in the field.

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Stem-cell therapy for cancer comes closer home - The New Indian Express

IPS Cell Therapy Comments Off on Stem-cell therapy for cancer comes closer home – The New Indian Express | May 23rd, 2017

News

Published online 22 May 2017

Two teams of Arab and American researchers are tantalizingly close to generating primordial blood stem cells in the lab.

Louise Sarant

Hematopoietic stem and progenitor cells (HSPC) from human iPS cells. Rio Sugimura Two teams of scientists have developed methods that make lab-grown blood stem cells a realistic prospect a goal for hematology researchers since human embryonic stem (ES) cells were first isolated in 1998.

Scientists have previously succeeded in genetically reprogramming skin cells to make pluripotent stem (iPS) cells, which are later used to generate multiple human cell types. However, the ability to induce blood stem cells that self-regenerate, for the treatment of millions affected by blood cancers and genetic disorders, has eluded researchers.

The two papers newly published in Nature describe methods that pave the way for safe, artificial and bona fide hematopoietic stem cells (HSCs) generation. Hematopoietic stem (HSC) cells are the common ancestor of all cells created in the body, producing billions of blood cells every day.

This bears major implications for cell therapy, drug screening and leukemia research. The root causes of blood diseases can be scrutinized and creating immune-matched blood cells, derived from a patients own cells, is now conceivable.

The first team, based at the Boston Childrens Hospital, has generated blood-forming stem cells (HSCs) in the lab using pluripotent stem cells for the first time.

Were tantalizingly close to generating bona fide human blood stem cells in a dish, says senior investigator George Daley, who heads the research lab in Boston Childrens Hospitals stem cell program and who is dean of Harvard Medical School. This work is the culmination of over 20 years of striving.

Ryohichi Rio Sugimura, the studys first author and a postdoctoral fellow in the Daley Lab, says his team exposed human pluripotent stem cells (both ES and iPS cells) to chemical signals to prompt them to differentiate into specialized cells and tissues during embryonic development.

"Sugimura and his colleagues delivered transcription factors proteins that control and regulate the transcription of specific genes into the cells using a lentivirus, a vector to deliver genes. The resultant cells were transplanted to immune deficient mice, where human blood and immune cells were made, he says.

A few weeks after the transplant, a small number of rodents were found to be carrying multiple types of blood cells in their bone marrow and blood; cells that are also found in human blood. This is a major step forward for our ability to investigate genetic blood disease, says Daley.

The second team, a group of scientists from Weill Cornell Qatar and Weill Cornell Medicine in New York, used mature mouse endothelial cells cells that line blood vessels as their starting material for generating HSCs.

Image of human CD45+ blood cells differentiated from iPS cells. Rio Sugimura Based on previous work, we hypothesized that endothelial cells are the mastermind of organ development, explains Jeremie Arash Rafii Tabrizi, paper co-author and researcher at the stem cell and microenvironment laboratory at Weill Cornell Medicine, Qatar.

The team isolated the cells, and then pushed key transcription factors into their genomes. Between days 8 and 20 into the process, the cells specified and multiplied.

Our research showed that endothelial cells can be converted into competent HSCs with the ability to both regenerate the myeloid and lymphoid lineage, he explains.

The method brings hope for people afflicted with leukemia requiring HSCs transplantation, or genetic disorders affecting the myeloid or lymphoid lineages. The clinical generation of HSCs, derived from the same individual, can eventually help scientists correct genetic abnormalities.

As exciting as the two studies are, rigorous tests are still required to check the normality of lab-grown cells before the clinical phase, says Alexander Medvinsky, professor of hematopoietic stem cell biology at the University of Edinburgh Medical Research Council Centre for Regenerative Medicine. Medvinsky was not involved in either study.

The risks of infusion of genetically engineered cells in humans should not be underestimated, he weighs in. Tests and trials to generate safe fully functional human blood stem cells may take many years, in contrast to similar assessment in short-living mice. It is not clear now whether blood stem cells can become cancerous in the longer term.

He adds however that this type of research is exactly what is required to potentially meet clinical needs.

doi:10.1038/nmiddleeast.2017.89

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Lab-grown blood stem cells - Nature Middle East

IPS Cell Therapy Comments Off on Lab-grown blood stem cells – Nature Middle East | May 22nd, 2017

Inquirer.net

Approaching a decades-old goal: Making blood stem cells from patients' own cells Science Daily ... lab using pluripotent stem cells, which can make virtually every cell type in the body. The advance opens new avenues for research into the root causes of blood diseases and to creating immune-matched blood cells for treatment purposes, derived ... 'Milestone' in quest to make blood cells studiesInquirer.net all 21 news articles »

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Approaching a decades-old goal: Making blood stem cells from patients' own cells - Science Daily

IPS Cell Therapy Comments Off on Approaching a decades-old goal: Making blood stem cells from patients’ own cells – Science Daily | May 18th, 2017

2016.09.20 MEDIAAlvetex wins CV Technology Innovator Awards 2016

ReproCELL is proud to announce its groundbreaking 3D cell culture technology Alvetex has been awarded the Corporate Vision Technology Innovator Award 2016. Read the full interview with Prof. Dr. Stefan Przyborski, ReproCELL Europes Chief Scientific Officer and inventor of Alvetex, here: http://reinnervate.com/reprocell-europe-wins-cv-tech-innovator-awards-2016-alvetex/

We will exhibit and presentat a poster at ISSCR 2016 Annual Meeting, San Francisco, USA. We will like to welcome you to stop by our booth and posters. ISSCR 2016 Annual Meeting URL http://www.isscr.org/home/annual-meeting/san-francisco-2016 Date JUNE 22-25, 2016 Place San Francisco, America Booth: Date JUNE 22-25, 2016 Booth No. 1608 POSTER Date & Time JUNE 22, 2016630PM730PM Poster No. Poster W1093 Title Improvement of human iPS cell-derived hepatocyte functionality using 3D culture systems Presenter ReproCELL, Inc. Zachary Yu Ching Lin Date & Time JUNE 22, 2016730PM830PM Poster No. Poster W2064 Title Non-modified RNAs for the derivation of clinically relevant iPS cell lines from adult []

We make the presentation a poster at 11th International ISSX Meeting at Busan, Korea. Please stop by at our poster if you attend to the meeting. 11th International ISSX Meeting URL http://issxbusan2016.org/ Date June 12-16, 2016 Place Busan, Korea POSTER Date June 15, 201612151300Poster session 2 Location Exhibit Hall (Grand Ballroom 3F) Poster No. P52 Title Stabilized and Enhanced CYP450 Enzyme Activity in Cultured Human Primary Hepatocytes is Conferred by ReproHP Medium Host Sales & Marketing DepartmentPaul CIZDZIEL Wirtz Julia POSTER Date June 15, 201612151300Poster session 2 Location Exhibit Hall (Grand Ballroom 3F) Poster No. P232 Title Improving the prediction of oral bioavailability using fresh []

Webinar: iPSC derived Cells & hiPSC/ES media June 4th 2013 10 AM CEST Please register from here; https://attendee.gotowebinar.com/register/7334590631056470272

ReproCELLs iPS cell technology featured in NHK World news http://www3.nhk.or.jp/nhkworld/english/movie/feature201303211118.html

An article written jointly by Kyoto University and ReproCELL was published in Cell Rep. 2012 Nov 29;2(5):1448-60.. Small Molecule that Promotes Cardiac Differentiation of Human Pluripotent Stem Cells under Defined, Cytokine- and Xeno-free Conditions

ReproCELLs iPS cell business was widely introduced in Japanese TV news on Prof. Shinya Yamanakas Nobel Prize.

ReproCELLs iPS cell-derived cardiomyocytes, neurons and hepatocytes were introduced in Genetic Engineering & Biotechnology News (GEN). Jan 15, 2012 (Vol. 32, No. 2) Stem Cell Applications Hasten into the Clinic

An article in Genetic Engineering & Biotechnology News, Pharmas R&D Focus Shifting to Stem Cells -Investors Interest in These Cells Increases as Scientists Continue to Unleash Their Potential introduces ReproCELLs new cardiotoxicity assay using iPSCs, QTempo, as well as its neural stem cell research. Read the article

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ReproCELL - Stem Cell Innovation

IPS Cell Therapy Comments Off on ReproCELL – Stem Cell Innovation | May 14th, 2017

Cell potency is a cell's ability to differentiate into other cell types.[1][2] The more cell types a cell can differentiate into, the greater its potency. Potency is also described as the gene activation potential within a cell which like a continuum begins with totipotency to designate a cell with the most differentiation potential, pluripotency, multipotency, oligopotency and finally unipotency. Potency is taken from the Latin term "potens" which means "having power".

Totipotency is the ability of a single cell to divide and produce all of the differentiated cells in an organism. Spores and zygotes are examples of totipotent cells.[3] In the spectrum of cell potency, totipotency represents the cell with the greatest differentiation potential. Toti comes from the Latin totus which means "entirely".

It is possible for a fully differentiated cell to return to a state of totipotency.[4] This conversion to totipotency is complex, not fully understood and the subject of recent research. Research in 2011 has shown that cells may differentiate not into a fully totipotent cell, but instead into a "complex cellular variation" of totipotency.[5] Stem cells resembling totipotent blastomeres from 2-cell stage embryos can arise spontaneously in the embryonic stem cell cultures[6][7] and also can be induced to arise more frequently in vitro through down-regulation of the chromatin assembly activity of CAF-1.[8]

The human development model is one which can be used to describe how totipotent cells arise.[9] Human development begins when a sperm fertilizes an egg and the resulting fertilized egg creates a single totipotent cell, a zygote.[10] In the first hours after fertilization, this zygote divides into identical totipotent cells, which can later develop into any of the three germ layers of a human (endoderm, mesoderm, or ectoderm), into cells of the cytotrophoblast layer or syncytiotrophoblast layer of the placenta. After reaching a 16-cell stage, the totipotent cells of the morula differentiate into cells that will eventually become either the blastocyst's Inner cell mass or the outer trophoblasts. Approximately four days after fertilization and after several cycles of cell division, these totipotent cells begin to specialize. The inner cell mass, the source of embryonic stem cells, becomes pluripotent.

Research on Caenorhabditis elegans suggests that multiple mechanisms including RNA regulation may play a role in maintaining totipotency at different stages of development in some species.[11] Work with zebrafish and mammals suggest a further interplay between miRNA and RNA binding proteins (RBPs) in determining development differences.[12]

In September 2013, a team from the Spanish national Cancer Research Centre was able for the first time to make adult cells from mice retreat to the characteristics of embryonic stem cells, thereby achieving totipotency.[13]

In cell biology, pluripotency (from the Latin plurimus, meaning very many, and potens, meaning having power)[14] refers to a stem cell that has the potential to differentiate into any of the three germ layers: endoderm (interior stomach lining, gastrointestinal tract, the lungs), mesoderm (muscle, bone, blood, urogenital), or ectoderm (epidermal tissues and nervous system).[15] However, cell pluripotency is a continuum, ranging from the completely pluripotent cell that can form every cell of the embryo proper, e.g., embryonic stem cells and iPSCs (see below), to the incompletely or partially pluripotent cell that can form cells of all three germ layers but that may not exhibit all the characteristics of completely pluripotent cells.

Induced pluripotent stem cells, commonly abbreviated as iPS cells or iPSCs are a type of pluripotent stem cell artificially derived from a non-pluripotent cell, typically an adult somatic cell, by inducing a "forced" expression of certain genes and transcription factors.[16] These transcription factors play a key role in determining the state of these cells and also highlights the fact that these somatic cells do preserve the same genetic information as early embryonic cells.[17] The ability to induce cells into a pluripotent state was initially pioneered in 2006 using mouse fibroblasts and four transcription factors, Oct4, Sox2, Klf4 and c-Myc;[18] this technique, called reprogramming, earned Shinya Yamanaka and John Gurdon the Nobel Prize in Physiology or Medicine 2012.[19] This was then followed in 2007 by the successful induction of human iPSCs derived from human dermal fibroblasts using methods similar to those used for the induction of mouse cells.[20] These induced cells exhibit similar traits to those of embryonic stem cells (ESCs) but do not require the use of embryos. Some of the similarities between ESCs and iPSCs include pluripotency, morphology, self-renewal ability, a trait that implies that they can divide and replicate indefinitely, and gene expression.[21]

Epigenetic factors are also thought to be involved in the actual reprogramming of somatic cells in order to induce pluripotency. It has been theorized that certain epigenetic factors might actually work to clear the original somatic epigenetic marks in order to acquire the new epigenetic marks that are part of achieving a pluripotent state. Chromatin is also reorganized in iPSCs and becomes like that found in ESCs in that it is less condensed and therefore more accessible. Euchromatin modifications are also common which is also consistent with the state of euchromatin found in ESCs.[21]

Due to their great similarity to ESCs, iPSCs have been of great interest to the medical and research community. iPSCs could potentially have the same therapeutic implications and applications as ESCs but without the controversial use of embryos in the process, a topic of great bioethical debate. In fact, the induced pluripotency of somatic cells into undifferentiated iPS cells was originally hailed as the end of the controversial use of embryonic stem cells. However, iPSCs were found to be potentially tumorigenic, and, despite advances,[16] were never approved for clinical stage research in the United States. Setbacks such as low replication rates and early senescence have also been encountered when making iPSCs,[22] hindering their use as ESCs replacements.

Additionally, it has been determined that the somatic expression of combined transcription factors can directly induce other defined somatic cell fates (transdifferentiation); researchers identified three neural-lineage-specific transcription factors that could directly convert mouse fibroblasts (skin cells) into fully functional neurons.[23] This result challenges the terminal nature of cellular differentiation and the integrity of lineage commitment; and implies that with the proper tools, all cells are totipotent and may form all kinds of tissue.

Some of the possible medical and therapeutic uses for iPSCs derived from patients include their use in cell and tissue transplants without the risk of rejection that is commonly encountered. iPSCs can potentially replace animal models unsuitable as well as in-vitro models used for disease research.[24]

Recent findings with respect to epiblasts before and after implantation have produced proposals for classifying pluripotency into two distinct phases: "naive" and "primed".[25] The baseline stem cells commonly used in science that are referred as Embryonic stem cells (ESCs) are derived from a pre-implantation epiblast; such epiblast is able to generate the entire fetus, and one epiblast cell is able to contribute to all cell lineages if injected into another blastocyst. On the other hand, several marked differences can be observed between the pre- and post-implantation epiblasts, such as their difference in morphology, in which the epiblast after implantation changes its morphology into a cup-like shape called the "egg cylinder" as well as chromosomal alteration in which one of the X-chromosomes undergoes random inactivation in the early stage of the egg cylinder, known as X-inactivation.[26] During this development, the egg cylinder epiblast cells are systematically targeted by Fibroblast growth factors, Wnt signaling, and other inductive factors via the surrounding yolk sac and the trophoblast tissue,[27] such that they become instructively specific according to the spatial organization.[28] Another major difference that was observed, with respect to cell potency, is that post-implantation epiblast stem cells are unable to contribute to blastocyst chimeras,[29] which distinguishes them from other known pluripotent stem cells. Cell lines derived from such post-implantation epiblasts are referred to as epiblast-derived stem cells which were first derived in laboratory in 2007; it should be noted, despite their nomenclature, that both ESCs and EpiSCs are derived from epiblasts, just at difference phases of development, and that pluripotency is still intact in the post-implantation epiblast, as demonstrated by the conserved expression of Nanog, Fut4, and Oct-4 in EpiSCs,[30] until somitogenesis and can be reversed midway through induced expression of Oct-4.[31]

Multipotency describes progenitor cells which have the gene activation potential to differentiate into discrete cell types. For example, a multipotent blood stem cell is a hematopoietic celland this cell type can differentiate itself into several types of blood cell types like lymphocytes, monocytes, neutrophils, etc., but cannot differentiate into brain cells, bone cells or other non-blood cell types.

New research related to multipotent cells suggests that multipotent cells may be capable of conversion into unrelated cell types. In another case, human umbilical cord blood stem cells were converted into human neurons.[32] Research is also focusing on converting multipotent cells into pluripotent cells.[33]

Multipotent cells are found in many, but not all human cell types. Multipotent cells have been found in cord blood,[34] adipose tissue,[35] cardiac cells,[36] bone marrow, and mesenchymal stem cells (MSCs) which are found in the third molar.[37]

MSCs may prove to be a valuable source for stem cells from molars at 810 years of age, before adult dental calcification. MSCs can differentiate into osteoblasts, chondrocytes, and adipocytes.[38]

In biology, oligopotency is the ability of progenitor cells to differentiate into a few cell types. It is a degree of potency. Examples of oligopotent stem cells are the lymphoid or myeloid stem cells.[1] A lymphoid cell specifically, can give rise to various blood cells such as B and T cells, however, not to a different blood cell type like a red blood cell.[39] Examples of progenitor cells are vascular stem cells that have the capacity to become both endothelial or smooth muscle cells.

In cell biology, a unipotent cell is the concept that one stem cell has the capacity to differentiate into only one cell type. It is currently unclear if true unipotent stem cells exist. Hepatoblasts, which differentiate into hepatocytes (which constitute most of the liver) or cholangiocytes (epithelial cells of the bile duct), are bipotent.[40] A close synonym for unipotent cell is precursor cell.

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Cell potency - Wikipedia

IPS Cell Therapy Comments Off on Cell potency – Wikipedia | May 13th, 2017

Science Daily

Engineering human stem cells to model the kidney's filtration barrier on a chip Science Daily ... of kidney diseases and drug toxicities, and the stem cell-derived kidney podocytes we developed could even offer a new injectable cell therapy approach for regenerative medicine in patients with life-threatening glomerulopathies in the future ...

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Engineering human stem cells to model the kidney's filtration barrier on a chip - Science Daily

IPS Cell Therapy Comments Off on Engineering human stem cells to model the kidney’s filtration barrier on a chip – Science Daily | May 12th, 2017

Stem cell therapy is a type of cell therapy wherein cells are introduced into the damaged tissue so as to treat the disorder or the injury. There are a number of medical researchers who believes that the stem cell therapy has the potential to change the treatment of human diseases and reduce the suffering people face when they have a disease. They believe that there are a lot of potential to replace the damaged and diseased tissues in the body without getting the risk of rejections.

The stem cells have the ability to self-renew and also give rise to further generation of cells that can multiply. There are a number of stem cell therapies that do exist but most of them are still in the experimental stages. The treatments are very costly with an exception of bone marrow transplant. However, researchers believe that one day they will be able to develop technologies from embryonic stem cells and also adult stem cells to cure type I diabetes, cancer, Parkinsons disease, cardiac failure, neurological disorders and many more such ailments.

The stem cell therapy however carries its own pros and cons and like any other therapy it cannot be said that the stem cell therapy is an advantageous package. Here are some of the pros and cons of the therapy.

Pros of the stem cell therapy include:

It offers a lot of medical benefits in the therapeutic sectors of regenerative medicine and cloning.

It shows great potential in the treatment of a number of conditions like Parkinsons disease, spinal cord injuries, Alzheimers disease, schizophrenia, cancer, diabetes and many others.

It helps the researchers know more about the growth of human cells and their development.

In future, the stem cell research can allow the scientists to test a number of potential medicines and drugs without carrying out any test on animals and humans. The drug can be tested on a population of cells directly.

The stem cell therapy also allows researchers to study the developmental stages that cannot be known directly through the human embryo and can be used in the treatment of a number of birth defects, infertility problems and also pregnancy loss. A higher understanding will allow the treatment of the abnormal development in the human body.

The stem cell therapy puts into use the cells of the patients own body and hence the risk of rejection can be reduced because the cells belong to the same human body.

The cons of the stem cell therapy include the following:

The use of the stem cells for research involves the destruction of the blastocytes that are formed from the laboratory fertilization of the human egg.

The long term side effects of the therapy are still unknown.

The disadvantage of adult stem cells is that the cells of a particular origin would generate cells only of that type, like brain cells would generate only brain cells and so on.

If the cells used in the therapy are embryonic then the disadvantage is that the cells will not be from the same human body and there are chances of rejection.

The stem cell therapy is still under the process of research and there are a number of things that needs to be established before it used as a treatment line.

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Pros and Cons of Stem Cell Therapy - Health Guidance

IPS Cell Therapy Comments Off on Pros and Cons of Stem Cell Therapy – Health Guidance | May 12th, 2017

Harvard Gazette

Researchers work to create kidney filtration barrier on a chip ... Harvard Gazette Researchers say their glomerulus-on-a-chip lined by human stem cell-derived kidney cells could help model patient-specific kidney diseases and guide ... and more »

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Researchers work to create kidney filtration barrier on a chip ... - Harvard Gazette

IPS Cell Therapy Comments Off on Researchers work to create kidney filtration barrier on a chip … – Harvard Gazette | May 12th, 2017

Shinya Yamanaka ( , Yamanaka Shin'ya?, born September 4, 1962) is a Japanese Nobel Prize-winning stem cell researcher.[1][2][3] He serves as the director of Center for iPS Cell (induced Pluripotent Stem Cell) Research and Application and a professor at the Institute for Frontier Medical Sciences(ja) at Kyoto University; as a senior investigator at the UCSF-affiliated J. David Gladstone Institutes in San Francisco, California; and as a professor of anatomy at University of California, San Francisco (UCSF). Yamanaka is also a past president of the International Society for Stem Cell Research (ISSCR).

He received the 2010 BBVA Foundation Frontiers of Knowledge Award in Biomedicine category. Also he received the Wolf Prize in Medicine in 2011 with Rudolf Jaenisch;[6] the Millennium Technology Prize in 2012 together with Linus Torvalds. In 2012 he and John Gurdon were awarded the Nobel Prize for Physiology or Medicine for the discovery that mature cells can be converted to stem cells.[7] In 2013 he was awarded the $3 million Breakthrough Prize in Life Sciences for his work.

Yamanaka was born in Higashisaka Japan in 1962. After graduating from Tennji High School attached to Osaka Kyoiku University,[8] he received his M.D. at Kobe University in 1987 and his PhD at Osaka City University Graduate School in 1993. After this, he went through a residency in orthopedic surgery at National Osaka Hospital and a postdoctoral fellowship at the Gladstone Institute of Cardiovascular Disease, San Francisco.

Afterwards he worked at the Gladstone Institutes in San Francisco, USA and Nara Institute of Science and Technology in Japan. Yamanaka is currently a Professor at Kyoto University, where he directs its Center for iPS Research and Application. He is also a senior investigator at the Gladstone Institutes as well as the director of the Center for iPS Cell Research and Application(ja).[9]

Between 1987 and 1989, Yamanaka was a resident in orthopedic surgery at the National Osaka Hospital. His first operation was to remove a benign tumor from his friend Shuichi Hirata, a task he could not complete after one hour when a skilled surgeon would have taken ten minutes or so. Some seniors referred to him as "Jamanaka", a pun on the Japanese word for obstacle.[10]

From 1993 to 1996, he was at the Gladstone Institute of Cardiovascular Disease. Between 1996 and 1999, he was an assistant professor at Osaka City University Medical School, but found himself mostly looking after mice in the laboratory, not doing actual research.[10]

His wife advised him to become a practicing doctor, but instead he applied for a position at the Nara Institute of Science and Technology. He stated that he could and would clarify the characteristics of embryonic stem cells, and this can-do attitude won him the job. From 19992003, he was an associate professor there, and started the research that would later win him the 2012 Nobel Prize. He became a full professor and remained at the institute in that position from 20032005. Between 2004 and 2010, Yamanaka was a professor at the Institute for Frontier Medical Sciences.[11] Currently, Yamanaka is the director and a professor at the Center for iPS Cell Research and Application at Kyoto University.

In 2006, he and his team generated induced pluripotent stem cells (iPS cells) from adult mouse fibroblasts.[1] iPS cells closely resemble embryonic stem cells, the in vitro equivalent of the part of the blastocyst (the embryo a few days after fertilization) which grows to become the embryo proper. They could show that his iPS cells were pluripotent, i.e. capable of generating all cell lineages of the body. Later he and his team generated iPS cells from human adult fibroblasts,[2] again as the first group to do so. A key difference from previous attempts by the field was his team's use of multiple transcription factors, instead of transfecting one transcription factor per experiment. They started with 24 transcription factors known to be important in the early embryo, but could in the end reduce it to 4 transcription factors Sox2, Oct4, Klf4 and c-Myc.[1]

Yamanaka practiced judo (2nd Dan black belt) and played rugby as a university student. He also has a history of running marathons. After a 20-year gap, he competed in the inaugural Osaka Marathon in 2011 as a charity runner with a time of 4:29:53. He also took part in the 2012 Kyoto Marathon to raise money for iPS research, finishing in 4:03:19. He also ran in the second Osaka Marathon on November 25, 2012.[12]

In 2007, Yamanaka was recognized as a "Person Who Mattered" in the Time Person of the Year edition of Time Magazine.[13] Yamanaka was also nominated as a 2008 Time 100 Finalist.[14] In June 2010, Yamanaka was awarded the Kyoto Prize for reprogramming adult skin cells to pluripotential precursors. Yamanaka developed the method as an alternative to embryonic stem cells, thus circumventing an approach in which embryos would be destroyed.

In May 2010, Yamanaka was given "Doctor of Science honorary degree" by Mount Sinai School of Medicine.[15]

In September 2010, he was awarded the Balzan Prize for his work on biology and stem cells.[16]

Yamanaka has been listed as one of the 15 Asian Scientists To Watch by Asian Scientist magazine on May 15, 2011.[17][18] In June 2011, he was awarded the inaugural McEwen Award for Innovation; he shared the $100,000 prize with Kazutoshi Takahashi(ja), who was the lead author on the paper describing the generation of induced pluripotent stem cells.[19]

In June 2012, he was awarded the Millennium Technology Prize for his work in stem cells.[20] He shared the 1.2 million euro prize with Linus Torvalds, the creator of the Linux kernel.

In October 2012, he and fellow stem cell researcher John Gurdon were awarded the Nobel Prize in Physiology or Medicine "for the discovery that mature cells can be reprogrammed to become pluripotent."[21]

The 2012 Nobel Prize in Physiology or Medicine was awarded jointly to Sir John B. Gurdon and Shinya Yamanaka "for the discovery that mature cells can be reprogrammed to become pluripotent."[22]

There are different types of stem cells

. These are some types of cells that will help in understanding the material.

totipotency remains through the first few cell divisions ex. the fertilised egg

The early embryo consists mainly of pluripotent stem cells

ex) blood multipotent cells can develop into various blood cells

Theoretically patient-specific transplantations possible

Much research done Immune rejection reducible via stem cell bank

Pluripotent

Abnormal aging

No immune rejection Safe (clinical trials)

The prevalent view during the early 20th century was that mature cells were permanently locked into the differentiated state and cannot return to a fully immature, pluripotent stem cell state. They thought that cellular differentiation can only be a unidirectional process. Therefore, non-differentiated egg/early embryo cells can only develop into specialized cells. However, stem cells with limited potency (adult stem cells) remain in bone marrow, intestine, skin etc. to act as a source of cell replacement.[23]

The fact that differentiated cell types had specific patterns of proteins suggested irreversible epigenetic modifications or genetic alterations to be the cause of unidirectional cell differentiation. So, cells progressively become more restricted in the differentiation potential and eventually lose pluripotency.[24]

In 1962, John B. Gurdon demonstrated that the nucleus from a differentiated frog intestinal epithelial cell can generate a fully functional tadpole via transplantation to an enucleated egg. Gurdon used somatic cell nuclear transfer (SCNT) as a method to understand reprogramming and how cells change in specialization. He concluded that differentiated somatic cell nuclei had the potential to revert to pluripotency. This was a paradigm shift during the time. It showed that a differentiated cell nucleus has retained the capacity to successfully revert to an undifferentiated state, with the potential to restart development (pluripotent capacity).

However, the question still remained whether an intact differentiated cell could be fully reprogrammed to become pluripotent.

Shinya Yamanaka proved that introduction of a small set of transcription factors into a differentiated cell was sufficient to revert the cell to a pluripotent state. Yamanaka focused on factors that are important for maintaining pluripotency in embryonic stem (ES) cells. Knowing that transcription factors were involved in the maintenance of the pluripotent state, he selected a set of 24 ES cell transcriptional factors as candidates to reinstate pluripotency in somatic cells.

First, he collected the 24 candidate factors. When all 24 genes encoding these transcription factors were introduced into skin fibroblasts, few actually generated colonies that were remarkably similar to ES cells. Secondly, further experiments were conducted with smaller numbers of transcription factors added to identify the key factors, through a very simple and yet sensitive assay system. Lastly, he identified the four key factors. They found that 4 transcriptional factors (Myc, Oct3/4, Sox2 and Klf4) were sufficient to convert mouse embryonic or adult fibroblasts to pluripotent stem cells (capable of producing teratomas in vivo and contributing to chimeric mice).

These pluripotent cells are called iPS (induced pluripotent stem) cells; they appeared with very low frequency.

iPS cells can be selected by inserting the b-geo gene into the Fbx15 locus. The Fbx15 promoter is active in pluripotent stem cells which induce b-geo expression, which in turn gives rise to G418 resistance; this resistance helps us identify the iPS cells in a culture.

Moreover, in 2007, Yamanaka and his colleagues found iPS cells with germ line transmission (via selecting for Oct4 or Nanog gene). Also in 2007, they were the first to produce human iPS cells.

However, there are some difficulties to overcome. The first is the issue of the very low production rate of iPS cells, and the other is the fact that the 4 transcriptional factors are shown to be oncogenic.

Nonetheless, this is a truly fundamental discovery. This was the first time an intact differentiated somatic cell could be reprogrammed to become pluripotent. This opened up a completely new research field.

In July 2014, a scandal regarding the research of Haruko Obokata was connected to Yamanaka. He could not find the lab notes from the period in question [25] and was made to apologise.[26][27]

Since the original discovery by Yamanaka, much further research has been done in this field, and many improvements have been made to the technology. Here we[who?] discuss the improvements made to Yamanaka's research as well as the future prospects of his findings.

1. The delivery mechanism of pluripotency factors has been improved. At first retroviral vectors, that integrate randomly in the genome and cause deregulation of genes that contribute to tumor formation, were used. However, now, non-integrating viruses, stabilised RNAs or proteins, or episomal plasmids (integration-free delivery mechanism) are used.

2. Transcription factors required for inducing pluripotency in different cell types have been identified (e.g. neural stem cells).

3. Small substitutive molecules were identified, that can substitute for the function of the transcription factors.

4. Transdifferentiation experiments were carried out. They tried to change the cell fate without proceeding through a pluripotent state. They were able to systematically identify genes that carry out transdifferentiation using combinations of transcription factors that induce cell fate switches. They found trandifferentiation within germ layer and between germ layers, e.g., exocrine cells to endocrine cells, fibroblast cells to myoblast cells, fibroblast cells to cardiomyocyte cells, fibroblast cells to neurons

5. Cell replacement therapy with iPS cells is a possibility. Stem cells can replace diseased or lost cells in degenerative disorders and they are less prone to immune rejection. However, there is a danger that it may introduce mutations or other genomic abnormalities that render it unsuitable for cell therapy. So, there are still many challenges, but it is a very exciting and promising research area. Further work is required to guarantee safety for patients.

6. Can medically use iPS cells from patients with genetic and other disorders to gain insights into the disease process. - Amyotrophic lateral sclerosis (ALS), Rett syndrome, spinal muscular atrophy (SMA), 1-antitrypsin deficiency, familial hypercholesterolemia and glycogen storage disease type 1A. - For cardiovascular disease, Timothy syndrome, LEOPARD syndrome, type 1 and 2 long QT syndrome - Alzheimers, Spinocerebellar ataxia, Huntingtons etc.

7. iPS cells provide screening platforms for development and validation of therapeutic compounds. For example, kinetin was a novel compound found in iPS cells from familial dysautonomia and beta blockers & ion channel blockers for long QT syndrome were identified with iPS cells.

Yamanaka's research has opened a new door and the world's scientists have set forth on a long journey of exploration, hoping to find our cells true potential.[28]

In 2013, iPS cells were used to generate a human vascularized and functional liver in mice in Japan. Multiple stem cells were used to differentiate the component parts of the liver, which then self-organized into the complex structure. When placed into a mouse host, the liver vessels connected to the hosts vessels and performed normal liver functions, including breaking down of drugs and liver secretions. [29]

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Shinya Yamanaka - Wikipedia

IPS Cell Therapy Comments Off on Shinya Yamanaka – Wikipedia | May 10th, 2017

Induced pluripotent stem cells have revolutionized stem cell science in the decade since their invention. Theyre yielding clues into the nature of diseases such as cancer and Alzheimers, and are also being tapped for therapy.

But creating these IPS cells is lengthy, complicated and tricky, and the facilities equipped to make them cant accommodate all the scientists whod like to get their hands on them.

A UK-led consortium has removed that bottleneck, by producing 711 lines of ready-to-go IPS cells from healthy individuals. These lines are meant to help scientists understand the normal variations between healthy individuals and those involved in disease, as well as to understand normal human biology and development.

The IPS lines are available for research purposes to academic scientists and industry by contacting the Human Induced Pluripotent Stem Cell Initiative (HipSci), at http://www.hipsci.org and the European Bank for induced Pluripotent Stem Cells at https://www.ebisc.org.

The accomplishment was announced in a study published in Nature. It can be found online at j.mp/711ips.

While many other efforts have generated IPS cells to address rare diseases, this study produces them from healthy volunteers to plumb common genetic variation, Fiona Watt, a lead author on the paper and co-principal investigator of HipSci, from King's College London, said in a statement.

"We were able to show similar characteristics of iPS cells from the same person, and revealed that up to 46 per cent of the differences we saw in iPS cells were due to differences between individuals, Watt said in the statement. These data will allow researchers to put disease variations in context with healthy people."

Andrs Bratt-Leal, director of the Parkinson's Cell Therapy Program at The Scripps Research Institute in La Jolla, agreed.

This kind of study is extremely important because it leads to a deeper understanding of the differences between normal genetic variation and genetic changes that could negatively impact cell behavior, said Bratt-Leal, who was not involved in the study.

This data will help scientists using induced pluripotent stem cells to model diseases as well as scientists developing cell therapies, said Bratt-Leal, who works in the lab of stem cell researcher Jeanne Loring.

Because DNA sequencing has become a routine tool in the lab, enormous amounts of data have been produced, he said. Not only have we have observed a high level of genetic diversity between different people, but also a more subtle variation exists among the cells from an individual person. The next step is a better understanding of how this diversity translates to function and behavior of stem cells and mature cells derived from stem cells.

Loring and Bratt-Leal are studying the use of induced pluripotent stem cells to relieve symptoms of Parkinsons disease. They are in the process of translating the research into a therapy, aided with a grant from the California Institute for Regenerative Medicine.

The work was the product of a large-scale collaboration of scientists from various institutions in the United Kingdom, including the European Molecular Biology Laboratory in Cambridge; Wellcome Trust Sanger Institute in Cambridge; the University of Dundee in Dundee; and the University of Cambridge. Also participating was St Vincent's Institute of Medical Research in Victoria, Australia.

bradley.fikes@sduniontribune.com

(619) 293-1020

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1:00 p.m.: This article was updated with additional details.

This article was originally published at 10:00 a.m.

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Hundreds of new stem cell lines ready to help research - The San Diego Union-Tribune

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