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Embryonic stem cells are blank cells found in embryos, which have the ability to turn into any cell in the body.

Embryonic stem cells are blank cells found in embryos, which have the ability to turn into any cell in the body.

CNN.COM, January 23, 2009, by Miriam Falco — — Federal regulators have cleared the way for the first human trials of human embryonic stem-cell research, authorizing researchers to test whether the cells are safe to use in spinal injury patients, the company behind the trials announced Friday.

The tests could begin by summer, said Dr. Thomas Okarma, president and CEO of the Geron Corporation. The Food and Drug Administration has approved the trials, which will use human stem cells authorized for research by then-President George W. Bush in 2001.

The patients will be those with the most severe spinal cord injuries, called complete spinal cord injuries.

“A complete spinal cord injury has no hope of recovery below the injury,” Okarma told CNN. “This is significant because it’s the first clinical trial of a human embryonic-based product.” The primary purpose of the trial will be to see whether injecting these cells into patients is safe, but Okarma said researchers will also look for any signs of recovery. Scientists will monitor the patients for a year after the injections to see if they are regaining any function below the injured point.

“If there is any movement below the injury, they will measure that and record it,” he said.

The trials will involve eight to 10 patients who are completely paralyzed below the third to tenth vertebra, and who sustained their spinal cord injury within seven to 14 days. The tests will use stem cells cultured from embryos left over in fertility clinics, which otherwise would have been discarded.

Using the stem cells, researchers have developed cells called oligodendrocytes, which are precursors to nerve cells and which produce a protective layer around nerve cells known as myelin. Researchers will inject these nerve cells directly into the part of the spine where the injury occurred.

Embryonic stem cells are blank cells found in four- to five-day-old embryos, which have the ability to turn into any cell in the body. However, when stem cells are removed, the embryo is destroyed — which has made this one of the most controversial medical research fields in the past decade.

Federal research funds were prohibited for embryonic stem-cell research until August 2001, when Bush approved spending for research using only already-existing cell lines. Scientists later discovered that fewer than two dozen of those lines were useful for research, but abortion opponents opposed any legislation that would lift Bush’s restrictions, and Bush twice vetoed congressional efforts to roll back his rules.

President Obama is expected to loosen the restrictions, which many researchers and advocates have complained severely set back work toward curing disease such as Alzheimer’s, Parkinson’s and diabetes.

Okarma said Geron did not use any federal funding for its research, and that the Bush restrictions had “devastated the field.”

“People didn’t think this would happen for another five years,” Okarma said. “But it will happen soon, and it would have happened sooner if it weren’t for the ridiculous Bush policies.”

Geron owns patents on and licenses the procedure to make these stem cell lines. The company spent $45 million of its own to produce everything required to get approval for the upcoming trial, Okarma said.

At least two other companies have said they plan to begin conducting embryonic stem-cell tests in humans, but only Geron has received FDA approval. Another U.S. company, Reneuron, plans to conduct trials involving stem cells taken from fetal tissue in Britain this year. Other companies have developed stem cells from adult tissue, sidestepping the controversy.

In addition to producing stem cells to treat spinal cord injuries, Geron says, it has seven other types of cells derived from stem cells in its pipeline. Okarma said FDA scrutiny was stringent, and that researchers studied the cells in petri dishes and in animals before obtaining permission to test them in humans.

Getting approval was made harder and took longer because the FDA had no other peer-reviewed research outside of Geron’s to consult as it reviewed the proposal, he said.

The trials are not expected to start until summer, because many of the preparations could not begin until Geron had FDA approval, Okarma said. Researchers have to be educated about how to use the stem cells, how to prepare their laboratories for the research and how to read all the magnetic resonance imaging (MRI) of the patients in the same way.

“We [also] have to train surgeons how to inject the stem cells,” Okarma explained. His company even developed a device that is mounted to the operating table to help surgeons inject the stem cells.

Geron still has to select the four to seven sites for the clinical trials, Okarma said.

The first human embryonic stem cells were developed by Jamie Thomson at the University of Wisconsin-Madison in 1998.

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Graphic: stem-cell treatment for spinal injuries
(David Scharf/Science Photo Library)

Therapies based on human embryonic stem cells could be used to treat paralysis, Parkinson?s disease and diabetes

The UK Times.com, January 23, 2009, by Mark Henderson — Paralysed patients will this summer become the first people in the world to receive a therapy based on human embryonic stem cells, in a study that promises to open a new era for medicine, The Times has learnt.

The first human trial of the technology, which has huge potential to cure disease yet is considered unethical by “pro-life” groups because it involves destroying embryos, will today be cleared to proceed by US regulators.

The decision marks a sea-change in US government attitudes to stem cells, as President Obama prepares to lift restrictions imposed by President Bush that hampered progress in the field. Mr Obama pledged in his inaugural address to “restore science to its rightful place”, and to end White House obstruction of stem-cell research.

Today’s ruling by the Food and Drug Administration (FDA) will allow doctors to inject specialised spinal cells grown from embryonic tissue into patients who have just become paralysed from the chest down. It is hoped that the cell transplants will prompt regrowth of damaged nerves, restoring sensation and movement to people who would otherwise have been paralysed for life. The treatment will be used on people a week or two after they suffer their spinal injury; it cannot help those already paralysed.

A successful trial would transform the prospects of thousands of people for whom few treatment options currently exist. If results are positive, the therapy could be approved for wider use within three to five years.

Thomas Okarma, chief executive of the Geron Corporation, which developed the treatment, said: “This marks the beginning of what is potentially a new chapter in medical therapeutics — one that reaches beyond pills to a new level of healing: the restoration of organ and tissue function by the injection of healthy replacement cells. The ultimate goal is to achieve restoration of spinal cord function.”

Embryonic stem cells are master cells found in human embryos, which give rise to more than 200 specialised types of tissue in the adult body. They have vast medical potential, because the can be grown into any kind of tissue to replace cells damaged by injury or disease. Stem-cell therapies could eventually be used to treat conditions such as diabetes and Parkinson’s disease, as well as paralysis.

Use of embryonic stem cells, however, is contentious because they must be harvested from human embryos, which are destroyed in the process. This has raised moral objections from those who believe embryos have the same rights as living people and see the technology as unethical.

The issue is especially acute in the US, where it has become entwined with the fraught politics of abortion. Opposition to stem-cell research is led by the evangelical Christian lobby, whose influence prompted President Bush to ban most federal funding in 2001 — the Geron work was financed entirely by the private sector. Stem cell research is legal in Britain, where it is encouraged and funded by the Government.

Though the FDA is independent of the White House, the timing of its backing for the Geron trial is symbolic of the Obama Administration’s fresh approach. The new President is expected to start unwinding the funding ban as early as next week.

Polls suggest that most Americans support stem-cell research, and Congress has voted for more federal funding, but in 2006, President Bush used his first veto to block a Bill that would have delivered this. Dr Okarma said: “The people who will take part in our trials are currently walking around, like you and me. But the delay caused by the White House has meant that there are people out there who might have benefited, but who now cannot.”

Stem cell research has been hailed for the potential to revolutionize the future of medicine with the ability to regenerate damaged and diseased organs. On the other hand, stem cell research has been highly controversial due to the ethical issues concerned with the culture and use of stem cells derived from human embryos. This article presents an overview of what stem cells are, what roles they play in normal processes such as development and cancer, and how stem cells could have the potential to treat incurable diseases. Ethical issues are not the subject of this review.1

In addition to offering unprecedented hope in treating many debilitating diseases, stem cells have advanced our understanding of basic biological processes. This review looks at two major aspects of stem cells:

I. Three processes in which stem cells play a central role in an organism, development, repair of damaged tissue, and cancer resulting from stem cell division going awry.

II. Research and clinical applications of cultured stem cells: this includes the types of stem cells used, their characteristics, and the uses of stem cells in studying biological processes, drug development and stem cell therapy; heart disease, diabetes and Parkinson’s disease are used as examples.

What are stem cells?

Stem cells are unspecialized cells that have two defining properties: the ability to differentiate into other cells and the ability to self-regenerate.

The ability to differentiate is the potential to develop into other cell types. A totipotent stem cell (e.g. fertilized egg) can develop into all cell types including the embryonic membranes. A pleuripotent stem cell can develop into cells from all three germinal layers (e.g cells from the inner cell mass). Other cells can be oligopotent, bipotent or unipotent depending on their ability to develop into few, two or one other cell type(s).2

Self-regeneration is the ability of stem cells to divide and produce more stem cells. During early development, the cell division is symmetrical i.e. each cell divides to gives rise to daughter cells each with the same potential. Later in development, the cell divides asymmetrically with one of the daughter cells produced also a stem cell and the other a more differentiated cell.

Differentiation Potential Number of cell types Example of stem cell Cell types resulting from differentiation Source

Totipotential All Zygote (fertilized egg), blastomere All cell types [m1]

Pleuripotential All except cells of the embryonic membranes Cultured human ES cells Cells from all three germ layers [m2]

Multipotential Many Hematopoietic cells skeletal muscle,cardiac muscle, liver cells, all blood cells [m3]

Oligopotential Few Myeloid precursor 5 types of blood cells (Monocytes, macrophages, eosinophils, neutrophils, erythrocytes) [m4]

Quadripotential 4 Mesenchymal progenitor cell Cartilage cells, fat cells, stromal cells, bone-forming cells [m5]

Tripotential 3 Glial-restricted precursor 2 types of astrocytes, oligodendrocytes [m6]

Bipotential 2 Bipotential precursor from murine fetal liver B cells, macrophages [m7]

Unipotential 1 Mast cell precursor Mast cells [m8]

Nullipotential None Terminally differentiated cell e.g. Red blood cell No cell division

Table 1: Differential potential ranges from totipotent stem cells to nullipotent cells.
Compiled from information in sources shown

I. Stem cells are central to three processes in an organism: development, repair of adult tissue and cancer.

A. Stem cells in mammalian development

The zygote is the ultimate stem cell. It is totipotent with the ability to produce all the cell types of the species including the trophoblast and the embryonic membranes. Development begins when the zygote undergoes several successive cell divisions, each resulting in a doubling of the cell number and a reduction in the cell size. At the 32- to 64-cell stage each cell is called a blastomere.2 The blastomeres stick together to form a tight ball of cells called a morula. Each of these cells retains totipotential. The next stage is the blastocyst which consists of a hollow ball of cells; trophoblast cells along the periphery develop into the embryonic membranes and placenta while the inner cell mass develops into the fetus. Beyond the blastocyst stage, development is characterized by cell migration in addition to cell division. The gastrula is composed of three germ layers: the ectoderm, mesoderm and endoderm. The outer layer or ectoderm gives rise to the future nervous system and the epidermis (skin and associated organs such as hair and nails). The middle layer or mesoderm gives rise to the connective tissue, muscles, bones and blood, and the endoderm (inner layer) forms the gastrointestinal tract of the future mammal.

Early in embryogenesis, some cells migrate to the primitive gonad or genital ridge. These are the precursors to the gonad of the organism and are called germinal cells. These cells are not derived from any of the three germ layers but appear to be set aside earlier.

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Figure 1: Differentiation of Human Tissues
Source: http://stemcells.nih.gov/info/scireport/chapter1.asp

Stem cells in late development

As development proceeds, there is a loss of potential and a gain of specialization, a process called determination. The cells of the germ layers are more specialized than the fertilized egg or the blastomere. The germ layer stem cells give rise to progenitor cells (also known as progenitors or precursor cells). For example, a cell in the endoderm gives rise to a primitive gut cell (progenitor) which can further divide to produce a liver cell (a terminally differentiated cell).

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Hierarchy of stem cells during differentiation.2at each stage, differential potential decreases and specialization increases.
(* These are also called transit-amplifying cells)

Role of Progenitor Cells in Development

While there is consensus in the literature that a progenitor is a partially specialized type of stem cell, there are differences in how progenitor cell division is described. For instance, according to one source,3 when a stem cell divides at least one of the daughter cells it produces is also a stem cell; when a progenitor cell undergoes cell division it produces two specialized cells. A different source,2 however, explains that a progenitor cell undergoes asymmetrical cell division, while a stem cell undergoes symmetrical cell division.

The apparent inconsistency of these two versions illustrates the diversity and complexity of progenitor cells and their role in differentiation. This diversity is reflected in the nomenclature as well; progenitor cells are also called Transit-amplifying cells, Precursor cells, Progenitors, Lineage stem cells, and Tissue-determined stem cells.

The table below shows these complex stages:

Early in development:

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Late in development: type 1

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Late in development: type 2

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Table 2: Summarized from information in references 6 and 7.

The number of stem cells present in an adult is far fewer than the number seen in early development because most of the stem cells have differentiated and multiplied. This makes it extremely difficult to isolate stem cells from an adult organism, which is why scientists hope to use embryonic stem cells for therapy because embryonic stem cells are much easier to obtain.

B. The role of adult stem cells in tissue repair

During development, stem cells divide and produce more specialized cells. Stem cells are also present in the adult in far lesser numbers. The role of adult stem cells (also called somatic stem cells) is believed to be replacement of damaged and injured tissue. Observed in continually-replenished cells such as blood cells and skin cells, stem cells have recently been found in other tissue, such as neural tissue.

Organ regeneration has long been believed to be through organ-specific and tissue-specific stem cells. Hematopoietic stem cells were believed to replenish blood cells, stem cells of the gut to replace cells of the gut and so on. Recently, using cell lineage tracking, stem cells from one organ have been discovered that divide to form cells of another organ. Hematopoietic stem cells can give rise to liver, brain and kidney cells. This plasticity of adult stem cells has been observed not only under experimental conditions, but also in people who have received bone marrow transplants.4

Tissue regeneration is achieved by two mechanisms: (1) Circulating stem cells divide and differentiate under appropriate signaling by cytokines and growth factors, e.g. blood cells; and (2) Differentiated cells which are capable of division can also self-repair, e.g. hepatocytes, endothelial cells, smooth muscle cells, keratinocytes and fibroblasts. These fully differentiated cells are limited to local repair. For more extensive repair, stem cells are maintained in the quiescent state, and can then be activated and mobilized to the required site.5

For wound healing in the skin, epidermal stem cells and bone-marrow progenitor cells both contribute.6 Thus it is likely that organ-specific progenitors and hematopoietic stem cells are involved in repair, even for other organ repair.

Fundamental remaining questions regarding adult stem cells include: Does one common type of stem cell migrate to different organs and repair tissue or are there multiple types of stem cells? Does every organ have stem cells (some of which have not yet been discovered)? Are the stem cells programmed to divide a finite number of times or do they have unlimited cell proliferation capacity?

C. Role of stem cells in cancer

Ontogeny (development of an organism) and oncology (cancer development) share many common features. From the 1870s the connection between development and cancer has been reported for various types of cancers. Existence of “cancer stem cells” with aberrant cell division has also been reported more recently. The connection between cancer and development is clearly evident in teratocarcinomas.

As early as 1862, Virchow discovered that the germ cell tumor teratocarcinoma is made up of embryonic cells. In 1970, Stevens derived embryonal carcinoma cells from teratocarcinomas. A teratocarcinoma is a spontaneous tumor of germ cells that resembles development gone awry. This tumor may contain several types of epithelia: areas of bone, cartilage, muscle, fat, hair, yolk sac, and placenta. These specialized tissues are often adjacent to an area of rapidly dividing unspecialized cells. The teratocarcinomas are able to differentiate into normal mature cells when transplanted into another animal. This alternation between developmental and tumor cells status demonstrates how closely development and cancer are related.

McCulloch explored the connection between normal development of blood cells and leukemia.7 According to him, normal hematopoietic development requires the interaction of stem cell factor with its receptor, c-kit. A hierarchy of stem and progenitor cells differentiates and produces different sublineages of cells resulting from response to varied growth factors. Malignancies of the hematopoietic system originate from two sources: those with an increased growth in an early stem cell produce acute leukemia, while those that arise from a decreased response to death or differentiation in a stem cell produce chronic leukemia.

The present-day challenge is to decode the common molecular mechanism and genes involved in self-renewal for cancer cells and stem cells.8

II. Stem cells used in research and clinical applications

Rao and colleagues postulate that all stem cells, regardless of their origin, share common properties.9 These researchers have reviewed the literature for candidate “stemness” genes. They conclude that there are a set of candidate genes that are present in all stem cells and can serve as universal markers for stem cells. These code for proteins are involved in self-renewal and differentiation. In addition they predict some differences in gene expression between different populations of stem cells.

A. Types and characteristics of stem cells for culture:

Embryonic stem (ES) cells are obtained from the inner cell mass and cultured as illustrated:

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Figure 2: Embryonic stem cell culture
Source: http://www.stemcellresearchfoundation.org/WhatsNew/Pluripotent.htm

ES cells from mouse embryos have been cultured since the 1980s by various groups of researchers working independently.10 These pioneers established murine embryonic stem cells lines that could differentiate into several different cell types.11 ES cell lines have been established from other mammals (hamsters, rats, pigs, and cows). Thompson and colleagues at the University of Wisconsin reported isolation of primate ES cells in 1995 and human ES cells in 1998.12

ES cells are the best characterized of all the cultured stem cells. Properties of ES cells:13
(i) ES cells are pleuripotent, i.e. they have the ability to differentiate into cells derived from all three germ layers, but not the embryonic membranes.
(ii) ES cells are immortal i.e. cells proliferate in culture and have been maintained in culture for several hundred doublings. The advantage of maintaining stem cells in culture is that they are a source of a large number of cells in the undifferentiated state. So far other adult stem cells have not been maintained indefinitely.
(iii) ES cells maintain a normal karyotype (there are no major structural changes in the chromosomes)
(iv) ES cells display Oct-4 protein and other unique markers on the cell surface.

Generally, ES cells are maintained in culture on feeder cells (mouse fibroblast cells) There have been recent reports of ES cultured on feeder cell-free medium.14

ES cells can be induced to differentiate in vitro by culturing in suspension to form three-dimensional cell aggregates called embryoid bodies (EBs).15 The cells spontaneously differentiate into various cell types, e.g. neurons, cardiomyocytes, and pancreatic beta cells. The addition of growth factors to the culture directs differentiation to specific cell types. However, it is still challenging to isolate pure differentiated cell types.

Following injection of ES cells into immunodeficient mice, teratomas develop with derivatives of all three germ layers. This is a major disadvantage of using ES cells for cell therapy since any contaminating undifferentiated cells could give rise to cancer.

Embryonic germ cells Gearhart and colleagues originally derived stem cells from primordial germ cells.16 Cells cultured from the genital ridge of the human embryo have been isolated and cultured. These cells have a lesser capacity of proliferation than ES cells but have an advantage in that they are not tumorigenic, unlike ES cells.17

Embryonal carcinoma cells Embryonal carcinoma cell lines were first developed in 1967 by Ephrussi and colleagues from mouse teratomas, followed in 1975 by Fogh and Tempe from a human testicular teratocarcinoma. These cells are malignant relatives of ES and EG cells, which were used in many of the techniques to cultivate them. EC cells can differentiate under the right conditions and have a potential to be used for research and perhaps clinical applications.18 Once they differentiate they would not be expected to cause cancer, but these cells have not been studied as well as ES cells and are of limited use at present.

Adult or somatic stem cells The existence of hematopoietic stem cells was discovered in the 1960s, followed by the discovery of stromal cells (also called mesenchymal cells). Only in the 1990s did scientists confirm the reports of neural stem cells in mammalian brains. Since then stem cells have been found in the epidermis, liver and several other tissues.19

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Figure 4: Hematopoietic and Stromal stem cell differentiation
Source: http://stemcells.nih.gov/info/scireport/chapter5.asp

Adult stem cells offer hope for cell therapy to treat diseases in the future because ethical issues do not impede their use. In addition, if the patient’s own cells are used, immunological compatibility is not an issue. However, ES cells have been found to be superior for both differentiation potential and ability to divide in culture.

Two concepts are useful to describe characteristics of adult stem cells:

Plasticity is a newly recognized ability of stem cells to expand their potential beyond the tissue from which they are derived. For example, Dental pulp stem cells develop into tissue of the teeth but can also develop into neural tissue.20

Transdifferentiation is the direct conversion of one cell type to another,21 e.g. transdifferentiation of pancreatic cells into hepatic cells and vice versa has been reported in both animals and humans as has the transdifferentiation of blood cells into brain cells and vice versa.22

Cell fusion: ES cells can fuse in vitro with neuronal cells and with hematopoietic stem cells.17 This has started a new debate in adult stem cell plasticity, namely that some cells may have fused and the nucleus was reprogrammed instead of transdifferentiating.

Cord blood stem cells Cord blood, from the umbilical cord, was believed to be an alternate source of hematopoietic stem cells; however, it is impossible to obtain sufficient numbers of stem cells from most cord blood collections to engraft an adult of average weight. Development continues on techniques to increase the number of these cells ex vivo. Cord blood contains both hematopoietic and non-hematopoietic stem cells.23

B. Research and Clinical Applications of Cultured Stem Cells

What are the uses of Cultured Stem cells? The most prominent is cell therapy for treating conditions such as spinal cord injuries and for curing disease. Stem cells are used to investigate questions to further basic and clinical research. Here are the major applications to date:

1. Functional Genomic studies
In 1986, Gossler et al. reported using mouse ES cells to produce transgenic animals.24 Soon after, two landmark papers in the field of mouse genetics demonstrated the ability to manipulate a specific gene of ES cells.25 Combining these techniques, a specific gene can be introduced into ES cells to produce transgenic mice. This gene can be transmitted to their offspring through the germline. Today these techniques enable the study of the function of mammalian genes and proteins in the mouse (through introducing human histocompatibility genes into mice).26

2. Study of biological processes
Studies of biological processes, namely development of the organism and progress of cancer, are facilitated by the ability to trace stem cell fate. The spleen colony assay developed by Till and McCulloch is an example study of the development of blood cells. In this method single cells were injected into heavily irradiated mice so that all the hematopoietic cells in these mice originated from the original colony. Studies of this nature helped decipher the clonal origin of cancer,

3. Drug discovery and development
The combination of isolation and purification of mouse ES cells and genetic engineering techniques has led to the use of murine ES cells in drug discovery. With the sequencing of the human genome many potential targets of new drugs have been identified. Studies using human ES may follow those of murine ES cells.27 Interest in using stem cells as models for toxicology has also grown recently.28

4. Cell-based therapy
Cultured ES cells spontaneously form embryoid bodies containing different cell types from all three germ layers. The desired cells are isolated and cultured and the differentiated cells are then used for therapy. ES cells have been induced to differentiate into neurons, cardiomyocytes and endoderm cells.

The identification of hematopoietic stem cells in mice by Till and McCulloch in 1961 heralded the use of stem cell therapy.29 By 1999, 50 diseases had been treated by bone marrow and stem cell therapy with varying degrees of success,30 among them leukemia, breast cancer, inflammatory bowel disease and osteogenesis imperfecta (a bone disease) in humans. ES and adult stem cells now offer hope for reversing the symptoms of many diseases and conditions including cancer, neurodegenerative diseases, spinal cord injuries, and heart disease.

The following stem cell characteristics make them good candidates for cell-based therapies:31

i. Potential to be harvested from patients
ii. High capacity of cell proliferation in culture to obtain large number of cells from a limited source
iii. Ease of manipulation to replace existing non functional genes via gene transfer methods
iv. Ability to migrate to host’s target tissues, e.g. the brain
v. Ability to integrate into host tissue and interact with surrounding tissue

Following is a summary of three diseases in which stem cell-based therapy has been used.

a) Heart disease
Cardiovascular disease is a leading cause of death worldwide killing 17 million people each year,32 especially due to heart attack and stroke. In the United States, heart disease is the number one cause of death. The high rate of mortality associated with heart diseases is the inability to repair damaged tissue33 due to the full differentiation of heart tissue. Interruption of blood supply to the tissue causes infarction of the myocardium and death of myocardiocytes.

A recent report used a swine model of atrioventricular block and transplanted human ES cell-derived cardiomyocytes into the pig’s heart to work as a pacemaker.34 The ES cells survived, functioned and integrated well with the host cells. The researchers used embryoid bodies to select spontaneously beating areas of culture (cultured myocytes will actually beat in synchrony just like a heartbeat). This study bodes well for future myocardial regeneration using human ES cells.

Adult stem cells have also been used in cell therapy for the heart.35 Skeletal muscle myoblast transfers showed contraction but did not differentiate into cardiomyocytes and did not integrate with the host myocardium. Ideally, both contraction and integration with host myocardium should have occurred in order for the therapy to be effective. Endothelial progenitor cells transplants halted the degenerative process but did not initiate regeneration. Early clinical studies may soon follow.

Another approach is cardiac tissue engineering.36 Cohen and Leor grew embryonal heart cells in vitro with an alginate scaffold (alginate is an algal polysaccharide) to provide 3D-support and organization for the cells. They transplanted the cells with the scaffold into the scar tissue of the rats with myocardial infarction and observed extensively. The vascularization shows that there was acceptance of the engineered tissue. This unique method of treating heart disease is promising and may be explored in other animal models in the future.

b) Diabetes
Elevated glucose levels in the blood are responsible for diabetes. Diabetes affects 16 million Americans (5.9 percent of the population) and is the seventh leading cause of death.37 Worldwide it afflicts 120 million people and the World Health Organization estimates that the number will reach 300 million by 2025.38 Type I diabetes, or juvenile onset diabetes, is an autoimmune disease that causes destruction of the insulin-producing beta cells in the pancreas. Insulin injections are given to diabetics but they cause surges in blood glucose levels followed by a drop in the glucose levels and lack fine tuning. Pancreas transplantation has been performed in diabetics as more recently has pancreatic islet cell transplantation. The latter has the advantages that it does not require whole organ transplantation. However, the need for immunosuppression to prevent rejection of allogeneic islet transplants and a serious shortage of organ donors are lingering problems.25 The Edmonton protocol, developed by Shapiro and colleagues, is promising. This procedure transplants a large amount of islet cells and uses a glucocorticoid-free type of immunosuppression regimen. In early clinical testing it reversed diabetes in all of the patients tested.

c) Stem cell therapy for diabetes
Cells need to be able to self-regenerate and differentiate. Also it has been observed that the presence of all the islet cell types is preferable to only beta cells since the former are better able to respond to changing levels of glucose in the blood. Growth must be balanced with ability to produce insulin. The insulin producing cells tend not to divide and those which divide actively do not produce insulin.

Adult stem cells from the pancreas have been elusive so far. However, a recent report of a clone from mouse pancreas that can generate both pancreatic and neural cell lines is exciting, as is a second report that adult small hepatocytes (liver cells) can be induced to produce insulin.39 Both reports offer hope for using adult stem cells as a treatment and cure for diabetes.

d) Parkinson’s Disease
Parkinson’s disease is the second most common neurodegenerative disease following Alzheimer’s. Approximately 1.5 million people in the United States suffer from Parkinson’s disease,40 which is caused when 80% or more of dopamine producing-neurons in the substantia nigra of the brain die. Normally, dopamine is secreted from the substantia nigra and transmitted to another part of the midbrain. This allows body movements to be smooth and coordinated.

ED9F495E-E269-4AAD-BBE4-0EE7E7D7E5EB.jpg
Figure 4: Stem Cell Transplant Research, Parkinson’s Disease
http://gslc.genetics.utah.edu/units/stemcells/scsuccess/1define.cfm

Patients with Parkinson’s disease are treated with the drug levodopa (or L-dopa), which is converted to dopamine in the body. Initially effective, the treatment’s success is reduced over time and side effects increase, leaving the patient helpless.41

It has been recognized that dopamine-producing cells are required to reverse Parkinson’s disease. Since the 1970s, many types of dopamine-producing cells have been used for transplantation. These include adrenal glands from the patient, human fetal tissue and fetal tissue from pigs.42 Limited success has been achieved with these cells. Rat and monkey models of Parkinson’s were used to test fetal mesencephalic cells.41 Success with animal models led to clinical trials.

Fetal tissue transplantation has been performed in 350 patients, including trials using pig fetal tissue. So far, the success of reversing Parkinson’s disease using fetal tissue has been limited at best. However, in the most successful cases, patients have been able to lead an independent life without L-dopa treatment.43 The limitations include (i) lack of sufficient tissue for the number of patients in need, (ii) variation in results between patients ranging from no benefit to reversal of symptoms, and (iii) Occurrence of uncontrolled flailing movements (called dyskinesias).

The many criteria for the cells used in therapy include the ability to produce dopamine, to divide and survive in the brain and to integrate into the host brain. For these reasons, differentiated embryonic stem cells offer more promise. Mouse ES cells have been used in rat models of Parkinson’s disease and recently human ES cells have been reported to differentiate into dopamine-producing neurons in culture.44

Another consideration is the immune problem. It was believed that the brain is an immunologically privileged site tolerating transplanted cells from a different individual (meaning that the immune system will not attack tissue transplanted into this location). However, a recent report challenges this view.45 For this reason autologous cells may offer a safer alternative. Neural stem cells and hematopoietic stem cells are both likely candidates.31 Also, dental pulp cells in both rats and humans produce neurotrophic factors and are a candidate for autologous transplantation in Parkinson’s.20

5) Therapeutic cloning
Somatic cell nuclear transfer was used to clone Dolly, the sheep.42 Since then, seven animal species have been cloned using this technique.44 A modified version for use in humans is as follows: The patient’s DNA is injected into an enucleated unfertilized egg and used to generate ES cells which are then cultured and allowed to differentiate, followed by transplantation into the patient. This technique is called therapeutic cloning. The use of such cells may bypass the ethical objections and immunological issues of using ES cells and is the future of stem-cell clinical application.

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Figure 5: Stem Cell Transplant Using a Patient’s Own Cells
http://gslc.genetics.utah.edu/units/stemcells/scfuture/

Conclusion

This review has summarized the role of stem cells in basic biological processes in vivo, namely in development, tissue repair and cancer in Part I. Part II focused on cultured stem cells and their uses, describing the different sources of stem cells, their properties and their research uses and clinical applications.

Remarkable progress has been achieved in studying stem cells. The most exciting use of cultured stem cells is the promise for curing many devastating diseases like Parkinson’s and diabetes. However, more basic research remains before stem-cell based therapy is widely used.

Of the stem cells discussed, ES cells have the most capacity to differentiate into a variety of cells and their proliferation capacity is also unsurpassed by any other cell type. There are three major problems with ES cells; ethical issues, immunological rejection problems and the potential of developing teratomas.

In the future, ideally, somatic stem cells from the patient will be extracted and manipulated and then reintroduced into the same patient to cure debilitating diseases. This would preclude the use of embryonic stem cells for cell therapy, eliminate the ethical objections against stem cell research, and also resolve immunological rejection problems. However, at present the cell proliferation and differentiation potential of embryonic stem cells remains far more likely to produce a cure than do the somatic cells. – authored by Preeti Gokal Kochar

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Claudia Castillo, 30, is getting back to normal life, six months after her landmark surgery.

CNN.COM — — “You’re going to speak with the miracle woman, right?” asks a neighbor as we search for her house, cameras in tow.

Claudia Castillo needs no introduction in these parts. She is known simply as the ‘wonder woman’ in her modest neighborhood in the Colombian city of Cali.

Since Claudia, 30, received a new windpipe with tissue engineered from her own stem cells, she has become something of a local celebrity, as well as the subject of intense media interest from around the world.

Her operation, carried out in Spain in June this year, was one of the most exciting medical advances of 2008.

The breakthrough allowed Claudia to receive a new section of trachea — an airway essential for breathing — without the risk that her body would reject the transplant.

Scientists hope it could revolutionize transplants in the future.

After contracting tuberculosis in 2004, the mother-of-two was left with a damaged trachea, which led to severe breathing difficulties.

She suffered from agonizing bouts of coughing that sometimes left her feeling like she was suffocating.

“It was a constant cough and shortness of breath,” Claudia, a dental assistant, tells CNN in an interview at her father’s house in her native city of Cali, southwest Colombia.

“Working, going shopping, household chores, being with my small daughter, or climbing stairs, I couldn’t do any of these things.”

As things grew progressively worse, earlier this year, Castillo was told by her doctors she had two options — have her left lung removed or undergo a transplant — that had only previously been carried out on pigs.

Doctors at the Hospital Clinic in Barcelona, Spain explained to Claudia that pigs are the closest to humans in terms of the lungs, heart and the bronchia.

“The doctor told me that they had operated on some pigs and wanted to know if I wanted to meet them. So, I met the pigs … and they were fine,” Claudia says.

“Dr Macchiarini told me that this was first time in the world that they would do this. There had been a lot of studies and the trachea was ready.

“As I had a lot of faith in the doctor for everything he did for me. It always turned out well, I decided I would go through with this.”

“Obviously I was very scared,” she says. “I thought that maybe the things wouldn’t work out.

“But at the same time as my fear, I had confidence in God and in the doctor that everything would work out well.”

Three months before the transplant, stem cells were removed from Claudia’s nose and hip in preparation for the six-hour operation that would change her life.

Now almost fully recovered, Claudia is trying to return to the active life she once led in Cali with her two children Johan, 15, and Isabella, four.

“Obviously, it’s a lot better, I can breathe better. Now I don’t feel like I’m suffocating. I’m trying to lead a normal life,” she says. “I can climb stairs, climb up hills. I haven’t been running yet, but I think I can.”

She’s also hoping to get back to swimming, a pastime she hasn’t been able to enjoy for more than three years.

But on the day of our interview, nearly six months after the operation, Claudia was having a bad day. She was suffering from one of her periodic coughing fits, a series of convulsions that sounded so raw I winced.

As she talked there was a noticeable shortness of breath; after a long string of words, she would silently gasp and swallow some air.

She blamed the coughing fit on the change of climate from a Spanish winter to the tropical warmth of Colombia. And it was an uncomfortably hot day in Cali that day, even if we were surrounded by early Christmas decorations.

Listening to her story, Claudia seemed to represent so many of the Colombians I had met before in this troubled country. A hard worker, she wanted to make a better life for her family, so joined the millions of her countrymen who have moved to Spain.

Like so many people in Colombia, the country’s rampant violence has scarred her family; a decade ago, her brother was killed in random violence.

As much as he wanted to be by her bedside during the operation, her father couldn’t get a visa to travel to Spain in time, another problem for Colombians who are routinely eyed with suspicion by immigration officers across the world.

But now she’s recognized on the street, with strangers thanking her for giving them hope.

“‘They say hello miracle girl, the wonder woman” People hug me, some people cry,” says Castillo.

“I feel good because it gives hope to sick people who haven’t been given any hope.”

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Claudia Castillo, 30, suffered from tuberculosis for years.

CNN.COM — Stem cells are considered a holy grail of medical research. They are thought to hold immense potential for treating a wide range of diseases and disabilities.

However, they have also been the source of much heated debate — particularly the use of embryonic stem cells.

In the case of Claudia Castillo, a 30-year-old Colombian mother of two living in Barcelona, her own adult stem cells have been used to grow a new section of trachea — an airway essential for breathing. It is a first and could revolutionize stem cell use.

What are stem cells?

Most adult cells in the body have a particular purpose that cannot be changed. For example, a liver cell has specific functions and cannot take on the roll of cells in other organs.

Stem cells are different. They retain the potential to turn into may types of different cells.

Why are they considered useful?

When a stem cell divides it has the potential to remain the same or become a cell with a more specialized function. Scientists believe this ability could be harnessed to turn them into a repair kit for the body.

They believe they could be used to grow healthy tissue — as in Claudia Castillo’s case — to replace parts of the body damaged or affected by disease.

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They also hope it could be used to treat conditions like Parkinson’s and Alzheimer’s, the after effects of strokes, arthritis, burns and spinal conditions.

What types of stem cells are used?

Scientists typically work with two kinds of stem cells: embryonic stem cells and adult stem cells, which have different functions and characteristics.

Till now, scientists have believed the most useful stem cells have come from embryos.

This is because embryonic cells are pluripotent — they have the ability to become any type of cell.

They have also been comparatively easy to grow in lab conditions, proving much more useful to researchers who require a large number of cells for replacement therapies.

However, stem cells are also found in adult organs and it is these cells that will now become the focus of more research. They are rarer and have been much harder to grow in the lab. They have been considered much less pluripotent.

The advantage of using adult stem cells is that they can be taken from the patient and then reintroduced, meaning rejection by the immune system is not a problem.

Is stem cell use controversial?

Yes, very. Some campaigners are fiercely opposed to the use of embryonic stem cells.

They are typically taken from lab-created embryos aged just four or five days, however, opponents argue they are living human beings and should not be used for experiments and destroyed.

Opposition to their use has been particularly vociferous in the U.S., where President George W. Bush banned the use of government funds for embryonic stem cell research.

However, most groups are supportive of adult stem cell research. So, this breakthrough represents a giant step.

What next?

The race is on to replicate the success with Castillo. In the past, because adult stem cells were considered stuck in their ways, the focus had been on embryonic cells but now scientists and doctors will be wanting to see if adult cells can be used to treat a wider range of conditions.

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Geron to Study GRNOPC1 in Patients With Acute Spinal Cord Injury

MENLO PARK, Calif.–(BUSINESS WIRE)–Jan 23, 2009 – Geron Corporation (Nasdaq:GERN) announced today that the U.S. Food and Drug Administration (FDA) has granted clearance of the company’s Investigational New Drug (IND) application for the clinical trial of GRNOPC1 in patients with acute spinal cord injury.

The clearance enables Geron to move forward with the world’s first study of a human embryonic stem cell (hESC)-based therapy in man. Geron plans to initiate a Phase I multi-center trial that is designed to establish the safety of GRNOPC1 in patients with “complete” American Spinal Injury Association (ASIA) grade A subacute thoracic spinal cord injuries.

“The FDA’s clearance of our GRNOPC1 IND is one of Geron’s most significant accomplishments to date,” said Thomas B. Okarma, Ph.D., M.D., Geron’s president and CEO. “This marks the beginning of what is potentially a new chapter in medical therapeutics – one that reaches beyond pills to a new level of healing: the restoration of organ and tissue function achieved by the injection of healthy replacement cells. The ultimate goal for the use of GRNOPC1 is to achieve restoration of spinal cord function by the injection of hESC-derived oligodendrocyte progenitor cells directly into the lesion site of the patient’s injured spinal cord.”

GRNOPC1, Geron’s lead hESC-based therapeutic candidate, contains hESC-derived oligodendrocyte progenitor cells that have demonstrated remyelinating and nerve growth stimulating properties leading to restoration of function in animal models of acute spinal cord injury (Journal of Neuroscience, Vol. 25, 2005).

“The neurosurgical community is very excited by this new approach to treating devastating spinal cord injury,” said Richard Fessler, M.D., Ph.D., professor of neurological surgery at the Feinberg School of Medicine at Northwestern University. “Demyelination is central to the pathology of the injury, and its reversal by means of injecting oligodendrocyte progenitor cells would be revolutionary for the field. If safe and effective, the therapy would provide a viable treatment option for thousands of patients who suffer severe spinal cord injuries each year.”

The GRNOPC1 Clinical Program

Patients eligible for the Phase I trial must have documented evidence of functionally complete spinal cord injury with a neurological level of T3 to T10 spinal segments and agree to have GRNOPC1 injected into the lesion sites between seven and 14 days after injury. Geron has selected up to seven U.S. medical centers as candidates to participate in this study and in planned protocol extensions. The sites will be identified as they come online and are ready to enroll subjects into the study.

Although the primary endpoint of the trial is safety, the protocol includes secondary endpoints to assess efficacy, such as improved neuromuscular control or sensation in the trunk or lower extremities. Once safety in this patient population has been established and the FDA reviews clinical data in conjunction with additional data from ongoing animal studies, Geron plans to seek FDA approval to extend the study to increase the dose of GRNOPC1, enroll subjects with complete cervical injuries and expand the trial to include patients with severe incomplete (ASIA grade B or C) injuries to enable access to the therapy for as broad a population of severe spinal cord-injured patients as is medically appropriate.

Preclinical Evidence of Safety, Tolerability and Efficacy

Geron submitted evidence of the safety, tolerability and efficacy of GRNOPC1 to the FDA in a 21,000-page IND application that described 24 separate animal studies requiring the production of more than five billion GRNOPC1 cells. Included in the safety package were studies that showed no evidence of teratoma formation 12 months after injection of clinical grade GRNOPC1 into the injured spinal cord of rats and mice. Other studies documented the absence of significant migration of the injected cells outside the spinal cord, allodynia induction (increased neuropathic pain due to the injected cells), systemic toxicity or increased mortality in animals receiving GRNOPC1.

In vitro studies have shown that GRNOPC1 is minimally recognized by the human immune system. GRNOPC1 is not recognized in vitro by allogeneic sera, NK cells or T cells (Journal of Neuroimmunology, Vol. 192, 2007). These immune-privileged characteristics of the hESC-derived cells allow a clinical trial design that incorporates a limited course of low-dose immunosuppression and provide the rationale for an off-the-shelf, allogeneic cell therapy.

Also included in the IND application were published studies supporting the utility of GRNOPC1 for the treatment of spinal cord injury. Those studies showed that administration of GRNOPC1 significantly improved locomotor activity and kinematic scores of animals with spinal cord injuries when injected seven days after the injury (Journal of Neuroscience, Vol. 25, 2005). Histological examination of the injured spinal cords treated with GRNOPC1 showed improved axon survival and extensive remyelination surrounding the rat axons. These effects of GRNOPC1 were present nine months after a single injection of cells. In these nine-month studies, the cells were shown to migrate and fill the lesion cavity, with bundles of myelinated axons crossing the injury site.

Production and Qualification of GRNOPC1

GRNOPC1 is produced using current Good Manufacturing Practices (cGMP) in Geron’s manufacturing facilities. Geron’s GRNOPC1 production process and clean-room suites have been inspected and licensed by the state of California. The cells are derived from the H1 human embryonic stem cell line, which was created before August 9, 2001. Studies using this line qualify for U.S. federal research funding, although no federal funding was received for the development of the product or to support the clinical trial.

Geron’s H1 hESC master cell bank is fully qualified for human use and was shown to be karyotypically normal and free of measurable contaminants of human or animal origin. Production of GRNOPC1 from undifferentiated hESCs in the master cell bank uses qualified reagents and a standardized protocol developed at Geron over the past three years. Each manufacturing run of GRNOPC1 is subjected to standardized quality control testing to ensure viability, sterility and appropriate cellular composition before release for clinical use. GRNOPC1 product that has passed all such specifications and has been released is available for the approved clinical trial. The current production scale can supply product needs through pivotal clinical trials. The existing master cell bank could potentially supply sufficient starting material for GRNOPC1 to commercially supply the U.S. acute spinal cord injury market for more than 20 years.

Intellectual Property

The production and commercialization of GRNOPC1 is protected by a portfolio of patent rights owned by or exclusively licensed to Geron. Patent rights owned by Geron protect key technologies developed at Geron for the scalable manufacturing of hESCs, as well as the production of neural cells by differentiation of hESCs. The fundamental patents covering hESCs are exclusively licensed to Geron from the Wisconsin Alumni Research Foundation (WARF) for the production of neural cells, cardiomyocytes and pancreatic islets for therapeutic applications. The validity of these patents was recently confirmed by the U.S. Patent and Trademark Office in a re-examination proceeding. Geron funded the original research at the University of Wisconsin-Madison that led to the first isolation of hESCs. The production of oligodendrocytes from hESCs is covered by patent rights exclusively licensed to Geron from the University of California. These patent rights

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FDA Approves 1st Stem Cell Study for Spinal Injury

PharmaLive.com, January 23, 2009 — A U.S. biotech company says it plans to start this summer the world’s first study of a treatment based on human embryonic stem cells _ a long-awaited project aimed at spinal cord injury.

The company gained federal permission this week to inject eight to 10 patients with cells derived from embryonic cells, said Dr. Thomas Okarma, president and CEO of Geron Corp. of Menlo Park, Calif.

The patients will be paraplegics, who can use their arms but can’t walk. They will receive a single injection within two weeks of their injury.

The study is aimed at testing the safety of the procedure, but doctors will also look for signs of improvement like return of sensation or movement in the legs, Okarma said.

Whatever its outcome, the study will mark a new chapter in the contentious history of embryonic stem cell research in the United States _ a field where debate spilled out of the laboratory long ago and into national politics.

While some overseas doctors claim to use human embryonic stem cells in their clinics, stem cell experts said they knew of no previous human studies that use such cells.

“It’s a milestone and it’s a breakthrough for the field” because Geron passed the safety hurdles for getting federal clearance to launch the study, said Ed Baetge, chief scientific officer of Novocell Inc. His company hopes to begin a similar human study for treating diabetes in a few years.

In addition, said spinal cord injury researcher Dr. Wise Young of Rutgers University, “a lot of hope of the spinal cord injury community is riding on this trial.”

Embryonic stem cells can develop into any cell of the body, and scientists have long hoped to harness them for creating replacement tissues to treat a variety of diseases. But research has been controversial because embryos must be destroyed to obtain them.

President Barack Obama has promised to relax the Bush administration’s restrictions on federal financing for such research. But Obama’s ascent to the White House had nothing to do with the U.S. Food and Drug Administration’s granting permission for the new study, Okarma said in a telephone interview Thursday.

In fact, the company says, the project involves stem cells that were eligible for federal funding under Bush, although no federal money was used to develop the experimental treatment or to pay for the human study.

Other human cells, called adult stem cells, have been tested before in people to treat heart problems, for example.

In the Geron study, the injections will be made in the spine at the site of damage. The work will be done in four to seven medical centers around the country, Okarma said.

Animal studies suggest that once injected, the cells will mature and repair what is essentially a lack of insulation around damaged nerves, and also pump out substances that nerves need to function and grow.

Apart from assessing safety, investigators will hope to see some signs of improvement in the patient, Okarma said. The idea is “not to make somebody … get up and dance the next day,” he said, but rather to provide some level of ability that can be improved by physical therapy.

Each patient will receive a low dose of anti-rejection drugs for about two months, because after that time the medications shouldn’t be needed, Okarma said. The study will follow each patient for at least a year.

Okarma said he can’t estimate how much such a therapy would cost if it proves effective, but that “this is not going to be a $500,000 price tag. It will be remarkably affordable … in the context of the value it provides.”

Evan Snyder, a stem cell researcher at the Burnham Institute for Medical Research in La Jolla, Calif., said scientists in the field will focus chiefly on the study’s results about safety.

“The one hope that everybody has is that nothing bad happens,” he said.

Geron Corp. has spent at least $100 million on human embryonic stem cell research. Founded in 1992, it does not have any therapies on the market.

However, the company is considered the world’s leading embryonic stem cell developer thanks to its claims on several key stem cell technologies. Geron helped finance researchers at the University of Wisconsin who first isolated human embryonic stem cells in 1998. The company has retained exclusive rights on several of those cell types.

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Microscopic view of embryonic stem cells.

The Washington Post, January 5, 2009, by Joel Garreau — The real news about the future of dentures is that there isn’t much of one. Toothlessness has declined 60 percent in the United States since 1960. Baby boomers will be the first generation in human history typically to go to their graves with most of their teeth.

And now comes tooth regeneration: growing teeth in adults, on demand, to replace missing ones. Soon.

This can’t be good for, among others, television news. Ever notice how much denture adhesive those programs still shill to geezers born too early for the fluoride revolution?

But gumming your groceries is yesterday’s news. This may be the last generation of third-graders to think it hilarious to say, “Your teeth are like stars — they come out at night.”

If you are one of those obedient souls who listened to your dentist and had your wisdom teeth removed for no particularly urgent reason, you are hosed.

If, however, you are one of those perverse rogues who refuses to fix anything that isn’t broken, hold everything! It turns out that wisdom teeth are prolific sources of the kind of adult stem cells needed to grow new teeth for you. From scratch. In your adult life, as you need them. In the near future. According to the National Institutes of Health.

For thousands of years, losing teeth has been a routine part of human aging. That’s over. “We’re there, right now,” says Pamela Robey. “A lot of people will go and never lose a tooth. With good health care and proper habits, there’s no reason to lose a tooth,” short of a knuckle sandwich.

Robey is chief of the Craniofacial and Skeletal Diseases Branch at the National Institute of Dental and Craniofacial Research, part of the NIH.

The introduction of cavity-preventing fluoride into drinking water and toothpaste is viewed as one of the 10 greatest public health accomplishments of the 20th century, right up there with vaccinations, according to the Centers for Disease Control and Prevention.

It did not occur without controversy. In the renowned 1964 black comedy “Dr. Strangelove,” Brig. Gen. Jack D. Ripper (Sterling Hayden) attacks the Soviet Union with nuclear-armed B-52s, hoping to thwart a Communist conspiracy to “sap and impurify” the “precious bodily fluids” of the American people with fluoridated water.

Leslie Seldin has some perspective on this. He graduated from dental school in 1966 and was the editor of “The Future of Dentistry,” a report published in 2001 by the American Dental Association.

“When I was growing up” — in the ’50s — “reaching the teen years you’d develop enormous amounts of decay,” he says. It wasn’t until the ’60s, when most baby boomers were growing up, that fluoridation really started having a major impact. By the ’90s, “if new patients came in that were young people, under 30, you really were surprised if you saw significant” cavities.

Fundamentally intact teeth, plus the increased attention paid to gum disease that can loosen them, have brought about a transformation.

“When I started out in dentistry, in my practice it wasn’t uncommon for people losing their teeth — you took out all their teeth and made a denture. You were working on a denture at all times,” says Seldin. “Now, five new dentures a year, that’s a lot. We go out of our way to avoid them.”

So what’s the future of dentures?

“Hopefully, they will become a relic,” says Mary MacDougall, director of the Institute of Oral Health Research at the University of Alabama. “Like Washington’s false teeth.”

Visions of Cuspids

If we no longer lose our teeth, will we lose our dreams about losing our teeth?

Teeth have great power in symbol and myth. Primitive people commonly adorn themselves with the teeth and claws of conquered animals. You still see shark-teeth necklaces on the chests of young beachgoers — usually male, presumably attempting to declare their virility.

“The tooth is the only part of the body that, as children, we get money for,” says Betty Sue Flowers of the University of Texas, who edited “The Power of Myth” by Joseph Campbell with Bill Moyers. “There’s no nail-clipping fairy. There’s no hair-cutting fairy.”

Since teeth are the archetypal means of attack, loss of one’s teeth in dreams signifies “a fear of castration or of complete failure in life,” reports J.E. Cirlot in “A Dictionary of Symbols,” the authoritative examination of the collective, social and religious meanings of images throughout history.

Freud thought that our extremely common tooth-loss dreams were about sexual guilt. Wow, was he predictable.

“Meaningful symbolic interpretation of teeth in dreams usually comes down to one idea: To lose teeth is to become vulnerable, to lose the first line of defense,” says Bernard Welt, professor of arts and humanities at the Corcoran College of Art and Design, where for 25 years he has taught a course about dreams.

“Thus it is not surprising if someone who feels defenseless or abandoned emotionally dreams of losing teeth.”

Yes, but does the end of tooth loss mean the end of tooth-loss dreams?

“To the extent that many dreams about losing teeth do seem to be inspired by seeing elderly people lacking teeth and incorporating that as a metaphor for mortality or aging or infirmity of later life, I think that proportion of the dreams would be expected to disappear,” says Deirdre Barrett of Harvard, editor of “The New Science of Dreaming.”

Welt is not so sure. “Obviously, people dream about being naked or partially clothed in public places — or about having to take an exam unprepared — without having these experiences,” he says.

And for all we know, the rarer tooth loss becomes, the more nightmarish it will be.

Rise Again

Regenerating a whole tooth is no less complicated than rebuilding a whole heart, says Songtao Shi of the University of Southern California, who heads a team working on creating such a tooth.

Not only do you have to create smart tissue (nerves), strong tissue (ligaments) and soft tissue (pulp), you’ve got to build enamel — by far the hardest structural element in the body. And you have to have openings for blood vessels and nerves. And you have to make the whole thing stick together. And you have to anchor it in bone. And then you have to make the entire arrangement last a lifetime in the juicy stew of bacteria that is your mouth.

It’s a nuisance, but researchers are closing in on it. In fact, they think the tooth will probably be the first complex organ to be completely regenerated from stem cells. In part this is because teeth are easily accessible — say ahhhhh. So are adult stem cells, found abundantly in both wisdom and baby teeth — no embryos required, and your immune system won’t reject your own cells.

Nobody is predicting when the first whole tooth will be grown in a human, although five to 10 years is a common guess. “The whole tooth — we’ve got a long way to go,” says Shi.

But his team is pursuing what he believes is a practical and immediate result: growing important parts of teeth that he thinks people will want to use right away. They’re working on creating a living root from scratch. “I think it will take a year,” Shi says. “Depends on how lucky we are, and how good we are.”

“How to make a root is real important,” says Robey. “Dentists say, ‘Give me a root and I can put a crown on it.’ ”

In addition, “we’re really, really close to treating periodontal disease with regeneration,” Shi says. Groups in Japan and Taiwan and at the University of Michigan are using stem cells to create hard and soft tissue in humans, he says. The idea is to take a tooth about to fall out and reconnect it firmly.

When you ask Shi how close we are to growing full teeth on demand, he laughs. But his crew has already created a living root using stem cells in a pig. “We did it. It works. We’re happy. We still have some questions to answer, but we’re working on it.”

He expects tooth regeneration “to be pretty common in the future.”

Oh, but that’s not the end of it.

How about genetically engineered teeth, like a shark’s?

For most children, the adult teeth are there just waiting to come in at the end of the useful life of the baby teeth. But some people, it turns out, have a genetic mutation that gives them a third set of teeth, which can be induced to erupt if the adult teeth are gone. “We have some great X-rays,” says dental researcher MacDougall.

Right now, that is seen as a genetic flaw to be eliminated. But some people see it as a great opportunity: We can learn how to genetically engineer extra teeth. This isn’t a bug, it’s a feature!

Toothful Culture

New word to know and tell: edentulous. It means having no teeth. Comes up a lot when you talk about West Virginians.

Sadly, the new world in which the CDC eventually expects all but 3 or 4 percent of us to be toothful is not arriving evenly distributed, researchers report. Poverty makes a difference, as do health education, access to quality dental care and culture.

When dental health types talk about “culture,” it seems they’re talking about what they find in the southern Appalachian highlands. West Virginia is not the poorest state in the union, nor is it even remotely the least educated. Yet a stunning 40.5 percent of all adults over 65 are edentulous, according to the CDC — more than twice the national average. Kentucky is second with 38.9 percent and Tennessee third with 34.9 percent.

“Certainly lifestyle is a piece of this — diet, exercise. On the obesity and smoking side, West Virginia ranks very, very high,” says Kenneth E. Thorpe, professor of health policy at Emory University and a consultant to the West Virginia legislature on health reform. He also points to “access to early-on primary care. Low-income kids don’t see the dentist ever.

“But all rural Appalachia — it goes back to lifestyle. Lack of exercise, poor diet. Just the fat intake during the day. Cheap, high-calorie fast food is abundant. West Virginia ranks very low on nutritional markers like vegetables, fruits. The diet is very different than in California, Colorado, Utah. And then there’s the lack of physical activity.”

Less clear is what the story is in a place as advanced as Britain. British teeth are so bad as to have become the stuff of modern legend. In the “Austin Powers” movies, the hero’s teeth are a running gag. Toothlessness among Brits over 65 exceeds that of West Virginia, reaching 46 percent, according to the World Health Organization. In Europe, this is a level exceeded only by the likes of Albania, Bulgaria and Bosnia-Herzegovina.

Plan Far Ahead

If you had been a great parent, like the University of Alabama’s MacDougall, you would have saved your children’s baby teeth in liquid nitrogen as sources of adult stem cells. So now MacDougall has the stem cells of her teenage sons — Morgan, 17, and Mason, 14 — from which to create future spare parts.

And you don’t.

Slacker.

When she moved from the University of Texas Health Science Center at San Antonio to her current position in Birmingham, she took with her the liquid nitrogen apparatus containing her sons’ baby-teeth stem cells. She insisted that the moving van have a generator to keep everything super-cold. And “they drove nonstop,” she says.

But that’s not the real test of great parenting. MacDougall didn’t actually save her children’s teeth in liquid nitrogen, she says. She took the teeth and extracted the soft residual tissue that holds the adult stem cells and put that in the liquid nitrogen.

Because she’s the kind of mom who cared enough to give the hard part of the teeth back to the boys.

So they could put them under the pillow for the tooth fairy.

New Scientist, January 23, 2009, by Andy Coghlan — Patients with spinal cord injuries will be first humans to receive repair cells derived from embryonic stem cells.

The first ever clinical trial using stem cells derived from embryonic stem cells (ESCs) received the go-ahead today from the US Food and Drug Administration.

Geron Corporation, a company based in Menlo Park, California, hopes to mend the spines of patients paralysed from the chest down by injecting injury sites with stem cells that restore connections and repair damage.

“This marks the beginning of what is potentially a new chapter in medical therapeutics, one that reaches beyond pills to a new level of healing: the restoration of organ and tissue function achieved by the injection of healthy replacement cells,” said the company’s president, Tom Okarma.

“My hat is off to Geron – this is what we’ve all been waiting for,” says Robert Lanza, chief scientist at Advanced Cell Technology, a stem cell company in Worcester, Massachusetts. “It’s been over a decade since embryonic stem cells were discovered, and this sends a message that we’re ready at last to start helping people.”

The trial had been “on clinical hold” for years over concerns that the cells could form tumours, but the FDA is now satisfied that this risk is low enough to allow the trial to proceed.
New political climate

Ethical concerns have also dogged the trial, because obtaining the cell lines involved destruction of embryos. The previous US president, George Bush, had obstructed research using such cells for eight years to appease his conservative supporters.

However, the new president, Barack Obama, promised in his inaugural address to “restore science to its rightful place”, so approval of the trial could be an early sign that he will lift all the Bush restrictions on stem-cell research, first imposed in 2001.

Hundreds of trials are already under way around the world with stem cells derived from adult or fetal tissue, but these cells are limited in the types of tissue they can turn into and repair.

The spine repair trial could open up a new era in medicine because embryonic stem cells are the only type that generate all 200 or so tissues of the body. To continue this story go to New Scientist at: http://www.newscientist.com/article/dn16475-historic-trial-to-treat-spinal-injury-with-stem-cells.html