Regenerative Medicine
Introduction

Human stem cells
Human stem cells

Regenerative medicine is the "process of replacing or regenerating human cells, tissues or organs to restore or establish normal function". This field holds the promise of regenerating damaged tissues and organs in the body by replacing damaged tissue and/or by stimulating the body's own repair mechanisms to heal previously irreparable tissues or organs. Regenerative medicine also empowers scientists to grow tissues and organs in the laboratory and safely implant them when the body cannot heal itself. Importantly, regenerative medicine has the potential to solve the problem of the shortage of organs available for donation compared to the number of patients that require life-saving organ transplantation. Depending on the source of cells, it can potentially solve the problem of organ transplant rejection if the organ's cells are derived from the patient's own tissue or cells.

Widely attributed to having first been coined by William Haseltine (founder of Human Genome Sciences), the term "Regenerative Medicine" was first found in a 1992 article on hospital administration by Leland Kaiser. Kaiser’s paper closes with a series of short paragraphs on future technologies that will impact hospitals. One such paragraph had ‘‘Regenerative Medicine’’ as a bold print title and went on to state, ‘‘A new branch of medicine will develop that attempts to change the course of chronic disease and in many instances will regenerate tired and failing organ systems.

Regenerative Medicine refers to a group of biomedical approaches to clinical therapies that may involve the use of stem cells. Examples include the injection of stem cells or progenitor cells (cell therapies); the induction of regeneration by biologically active molecules administered alone or as a secretion by infused cells (immunomodulation therapy); and transplantation of in vitro grown organs and tissues (Tissue engineering).

A form of regenerative medicine that recently made it into clinical practice, is the use of heparan sulfate analogues on (chronic) wound healing. Heparan sulfate analogues replace degraded heparan sulfate at the wound site. They assist the damaged tissue to heal itself by repositioning growth factors and cytokines back into the damaged extracellular matrix.

For example, in abdominal wall reconstruction (like inguinal hernia repair), biologic meshes are being used with some success.

Contents

1 Pioneers

2 Cord Blood and Regenerative Medicine

     o 2.1 Type 1 Diabetes

     o 2.2 Cardiovascular

     o 2.3 Central Nervous System

3 Heparan Sulfate Analogues

4 See also

5 References

6 External links

Pioneers

At the Wake Forest Institute for Regenerative Medicine, in North Carolina, Dr. Anthony Atala and his colleagues have successfully extracted muscle and bladder cells from several patients' bodies, cultivated these cells in petri dishes, and then layered the cells in three-dimensional molds that resembled the shapes of the bladders. Within weeks, the cells in the molds began functioning as regular bladders which were then implanted back into the patients' bodies.[14] The team is currently working on re-growing over 22 other different organs including the liver, heart, kidneys and testicles.

Dr. Stephen Badylak, a Research Professor in the Department of Surgery and director of Tissue Engineering at the McGowan Institute for Regenerative Medicine at the University of Pittsburgh, has developed a process which involves scraping cells from the lining of a pig's bladder, decellularizing (removing cells to leave a clean extracellular structure) the tissue and then drying it to become a sheet or a powder. This cellular matrix powder was used to re-grow the finger of Lee Spievak, who had severed half an inch of his finger after getting it caught in a propeller of a model plane. As of 2011, this new technology is being employed by the military to U.S. war veterans in Texas, as well as to some civilian patients. Nicknamed "pixie-dust," the powdered extracellular matrix is being used with great success to regenerate tissue lost and damaged due to traumatic injuries. For example, a 19-year old male patient who lost a significant amount of tissue on his heel after a fall from a cliff received two applications of the extracellular matrix powder at Kaiser Hospital in Roseville, California. His heel successfully regenerated, avoiding the necessity of bone and skin grafts, as well as other reconstructive surgery.

In June 2008, at the Hospital Clínic de Barcelona, Professor Paolo Macchiarini and his team, of the University of Barcelona, performed the first tissue engineered trachea (wind pipe) transplantation. Adult stem cells were extracted from the patient's bone marrow, grown into a large population, and matured into cartilage cells, or chondrocytes, using an adaptive method originally devised for treating osteoarthritis. The team then seeded the newly grown chondrocytes, as well as epithileal cells, into a decellularised (free of donor cells) tracheal segment that was donated from a 51 year old transplant donor who had died of cerebral hemorrhage. After four days of seeding, the graft was used to replace the patient's left main bronchus. After one month, a biopsy elicited local bleeding, indicating that the blood vessels had already grown back successfully.

In 2009 the SENS Foundation was launched, with its stated aim as "the application of regenerative medicine – defined to include the repair of living cells and extracellular material in situ – to the diseases and disabilities of ageing."

In 2012, Professor Paolo Macchiarini and his team improved upon the 2008 implant by transplanting a laboratory-made trachea seeded with the patient's own cells.

Cord Blood and Regenerative Medicine

Because a person’s own (autologous) cord blood stem cells can be safely infused back into that individual without being rejected by the body’s immune system — and because they have unique characteristics compared to other sources of stem cells — they are an increasing focus of regenerative medicine research.

The use of cord blood stem cells in treating conditions such as brain injury and Type 1 Diabetes is already being studied in humans, and earlier stage research is being conducted for treatments of stroke, and hearing loss.

Current estimates indicate that approximately 1 in 3 Americans could benefit from regenerative medicine, with autologous (the person’s own) cells, there is no risk of the immune system rejecting the cells, so physicians and researchers are only performing these potential cord blood therapies on children who have their own stem cells available.

Researchers are exploring the use of cord blood stem cells in the following regenerative medicine applications:

Type1 Diabetes

A clinical trial under way at the University of Florida is examining how an infusion of autologous cord blood stem cells into children with Type 1 diabetes will impact metabolic control over time, as compared to standard insulin treatments. Preliminary results demonstrate that an infusion of cord blood stem cell is safe and may provide some slowing of the loss of insulin production in children with type1 diabetes.

Cardiovascular

The stem cells found in a newborn’s umbilical cord blood are holding great promise in cardiovascular repair. Researchers are noting several positive observations in pre-clinical animal studies. Thus far, in animal models of myocardial infarction, cord blood stem cells have shown the ability to selectively migrate to injured cardiac tissue, improve vascular function and blood flow at the site of injury, and improve overall heart function.

Central Nervous System

Research has demonstrated convincing evidence in animal models that cord blood stem cells injected intravenously have the ability to migrate to the area of brain injury, alleviating mobility related symptoms. Also, administration of human cord blood stem cells into animals with stroke was shown to significantly improve behavior by stimulating the creation of new blood vessels and neurons in the brain.

This research also lends support for the pioneering clinical work at Duke University, focused on evaluating the impact of autologous cord blood infusions in children diagnosed with cerebral palsy and other forms of brain injury. This study is examining if an infusion of the child’s own cord blood stem cells facilitates repair of damaged brain tissue, including many with cerebral palsy. To date, more than 100 children have participated in the experimental treatment – many whose parents are reporting good progress. Another report published encouraging results in 2 toddlers with cerebral palsy where autologous cord blood infusion was combined with G-CSF.

As these clinical and pre-clinical studies demonstrate, cord blood stem cells will likely be an important resource as medicine advances toward harnessing the body’s own cells for treatment. The field of regenerative medicine can be expected to benefit greatly as additional cord blood stem cell applications are researched and more people have access to their own preserved cord blood.

On May 17, 2012, Osiris Therapeutics announced that Canadian health regulators approved Prochymal, a drug for acute graft-versus-host disease in children who have failed to respond to steroid treatment. Prochymal is the first stem cell drug to be approved anywhere in the world for a systemic disease. Graft-versus-host disease, a potentially fatal complication from bone marrow transplant, involves the newly implanted cells attacking the patient’s body.

See these references:

Regenerative Medicine, 2006 report, US National Institutes of Health

Cogle CR, Guthrie SM, Sanders RC, Allen WL, Scott EW, Petersen BE (August 2003). "An overview of stem cell research and regulatory issues". Mayo Clinic Proceedings 78 (8): 993–1003. doi:10.4065/78.8.993. PMID 12911047.

Center for Regenerative Medicine, More on history, healing potential and research activities on autologus stem cells technologies in regenerative medicine.

Metallo CM, Azarin SM, Ji L, de Pablo JJ, Palecek SP (June 2008). "Engineering tissue from human embryonic stem cells". Journal of Cellular and Molecular Medicine 12 (3): 709–29. doi:10.1111/j.1582-4934.2008.00228.x. PMC 2670852. PMID 18194458

Regenerative Medicine 2
Engineered Stem Cells

How Engineered Stem Cells May Enable Youthful Immortality

http://www.lef.org/magazine/mag2013/feb2013_otc_02.htm

Life Extension Magazine February 2013

How Engineered Stem Cells May Enable Youthful Immortality

by Michael D. West, PhD

(Intro by Life Extension)

What you are about to read is a blueprint by which newly developing technologies may be used to induce biological immortality in human beings.

This research goes far beyond what is normally published in Life Extension magazine.

When perfected, the research findings you are about to learn may enable doctors to inject progenitor cells that will regenerate every tissue in your body, thus restoring you to youthful health and vigor.

Some readers will find this article challenging to comprehend, but I encourage everyone to review it several times to understand how close we may be to achieving meaningful reversal of aging processes.

This article also contains new findings about how easy it is to increase your telomere length, which has been shown to confer longevity and protect against age-related disease.

Targeting the Clockwork of Cell Immortality: A Progress Report

There appears to be a consensus among gerontologists that a significant extension of the healthy human lifespan will require targeting of the clockworkmechanisms that cause aging. We will therefore attempt to explain what this means and what the implications may be for reversing biological aging.

Modern gerontology research can be divided into two camps. In the first camp, researchers are on a quest to understand and control the central mechanisms of the aging “clockwork”. This molecular machinery should be thought of as upstream central regulators (like telomeres) that subsequently trigger mechanisms further downstream. It is these downstream pathological mechanisms, such as chronic inflammation, that inflict age-related changes in specific tissues.

The second camp of researchers is focused on targeting molecules involved in these downstream mechanisms, as these factors (such as pro-inflammatory cytokines) are the “hatchet men” that directly trigger disease processes.

If we were to think of the individual mortal human as a ticking time bomb, the upstream mechanisms would be the clocking mechanism of the bomb, perhaps a ticking alarm clock or a burning fuse, and the downstream mechanisms would be the dynamite that is the most direct cause of the damage that follows. The first camp’s approach would therefore be to prevent the explosion itself by stopping the clock, whereas the second camp’s solution would be to let it explode but blunt the force of the explosion by covering it with a dump truck full of sand.

In humans, an example of an upstream clockwork mechanism would be the telomere clock of cellular aging, which counts off how many times a cell has divided and hence determines how old a cell really is. An example of a downstream mechanism would be an inflammatory process that leads to activation of damaging molecules in the coronary arteries as seen in atherosclerosis.

Many of the downstream processes are those typically addressed in Life Extension articles. This emphasis on the downstream may in part reflect the fact that our current understanding of many of the downstream mechanisms predates our understanding of the “upstream” clocking mechanisms. In addition, interventions into in these downstream events have favorably impacted the severity of age-related diseases.

However, most gerontologists agree that targeting the downstream mechanisms will not sufficiently extend human life expectancy to meet the objectives of those who seek aggressive solutions to pathological aging. By targeting upstream-biology—never before attempted in the practice of medicine—we could potentially create the most powerful impact on the aging process.

But first we should consider the basis for assuming that such a central clockwork exists, or that it would even be feasible to intervene in the inexorable progress of this ticking clock.

In this short progress report, we will attempt to describe the shortest path to a proof-of-principle by referring to a natural type of cellular immortality recently captured in the laboratory dish. This line of reasoning is now taking off in the scientific community.

We will then describe research funded in part by the Life Extension Foundation that has potential clinical application to combat the deadliest manifestation of cell mortality in the United States, namely, coronary artery disease . . . the leading cause of heart attack.

WHAT YOU NEED TO KNOW

Scientists Discover Novel Way to Reset Cellular Aging Clock • Pluripotent cells have the power to become a variety of cell types.
• Most somatic cells lack sufficient telomerase, and so every time somatic cells replicate, they progressively shorten their telomeres.
• Germ-line cells retain telomere length appropriate for the beginning of life, due to an abundance of telomerase activity.
• Telomerase, is an enzyme that synthesizes telomeres, a repeated sequence of DNA over and over again at the end of DNA strands needed to maintain cellular viability.
• Although telomeres typically shorten with aging, shortening is not inevitable and telomeres can also lengthen.
• Recent scientific studies have shown that reduced plasma levels of omega-6 fats coupled with increased omega- 3s resulted in an increase in telomere lengths.
• It is possible to utilize these advances to not only revert a cell in the body (somatic cell) back to the all-powerful pluripotent stem cell state, but also to activate telomerase and reset the clock of cell aging all the way back to the very beginning of life.


The Facts of Life

Let’s begin with the facts of life and remember how an individual human being comes to exist in the first place. The union of a sperm and egg cell leads to a unified cell commonly called a zygote, which then divides into two cells, then four, and so on, until a small cluster of cells form, each of which has the power to become any of the cell types in the human body.

Cells that have this power are said to be pluripotent, meaning they have power (-potent) to become a variety (plurality or pluri-) of cell types. These cells commit to the cell type they will eventually become, that is, each cell will commit to becoming a reproductive (sperm or egg) cell, or one of the body’s many life-functioning cell types such as muscle, blood, or brain cells. This process of cellular commitment is called differentiation.

If pluripotent cells differentiate into sperm or egg cells, scientists say they are remaining in the germ-line. The germ-line is that lineage of cells that connects the generations and is the biological basis of the immortality of the species. They are the cells whose continuous proliferation ensures there are always zebras in Africa. They are the reason why you can go to a local greenhouse and buy fresh young petunias to plant in your garden every spring, year after year. Germ-line cells have the amazing ability to spin off new individuals forever, without the limitations of aging.

When pluripotent germ-line cells commit to become one of the life-functioning cell types of the body, we say they have differentiated into somatic cells. This differentiation seals their fate. These somatic cells are now mortal, even though, up to this point, they have been proliferating continuously for billions of years as germ-line cells. They will now become part of the body that is programmed to die usually within 100 years. Those cells that went the germ-line route have the potential (though not certainty) that they may continue in future generations indefinitely. Because they are not committed to a mortal fate, scientists say the cells are immortal. The use of this term does not mean that the individual cells are indestructible, nor does it mean anything in a religious sense. Instead, the term simply refers to the lack of commitment to the mortality that occurs when these cells differentiate into somatic (functional) cells that have finite life spans, sometimes measured in maximum amount of doubling times before they die.

For the past few decades, scientists have focused on deciphering the molecular mechanisms of the immortality of germ-line cells in order to find a means of using those insights to restore health to aging somatic (life-sustaining functional) cells. In other words, we have attempted to find a means to rewind the clock of the “ticking time bomb” in our cells back to the beginning of life. In the past few years, we have learned that, when cells make the decision to become somatic (that is, cells that enable the body to function as opposed to reproductive germ-line cells) they turn off telomerase, an enzyme that synthesizes a repeated sequence of DNA over and over again at the end of DNA strands needed to maintain cellular viability. This region of the chromosomes is called telomeres, and we refer to it in this article as the “telomere clock of cellular aging”.

Most somatic cells lack sufficient telomerase, and so every time cells proliferate, they progressively shorten their telomeres. This functions as a clock mechanism not unlike the burning of a fuse. However, in contrast to somatic cells, germ-line cells retain telomere length appropriate for the beginning of life, due to an abundance of telomerase activity. Since there is currently no known way to safely and effectively extend telomere length in the body, our researchers have instead sought means to mimic the natural immortality of germ-line cells in the laboratory dish to make young and healthy cells of all kinds that could potentially be injected into the body. Using this approach, we might be able to repair tissues afflicted with age-related degenerative diseases. The good news is that this technology is now very much operational in the laboratory and is a focus of intensive research around the world.

REDUCED OMEGA-6 + INCREASED OMEGA-3 = EXTENDED TELOMERE LENGTH

Telomeres are the caps at the ends of chromosomes. Shorter telomeres have been linked with age-related disease and early death.13-16

Although telomeres typically shorten with aging, shortening is not inevitable and telomeres can also lengthen. Telomere length is associated with lifestyle behaviors. for instance, women who are obese or smoke cigarettes suffer greater loss of telomere length, with a corresponding reduction in life span.17,18

As this article was being finalized, a new study was published that measured telomere length in humans given EPA/DHA fish oil supplements. The results showed that reduced plasma levels of omega-6 fats coupled with increased omega-3s resulted in an increase in telomere lengths.19

The scientists attributed this telomere length increase to reductions in inflammatory cytokines and oxidative stress brought on by higher levels of omega-3s in relationship to pro-inflammatory omega-6s. Omega-6 fats to avoid include corn, sunflower, and safflower oils, along with arachidonic acid found in red meat and egg yolks. olive oil, rich in monounsaturated fats, should be substituted for omega-6 oils whenever possible. Dietary sources of omega-3s include cold-water fish, walnuts, and flax seed.

In this human study where telomeres were lengthened, scientists used between 1,250 and 2,500 mg of EPA/DHA fish oil daily to boost omega-3 plasma levels in relation to omega-6s.19

Life Extension members typically consume 2,400 mg of EPA/DHA daily in their fish oil supplement.

Embryonic Stem Cells

The first step in understanding how germ-line cell immortality could be used to regenerate aging tissues in the human body was to capture the cells in the laboratory dish. In the mid 1990s, in collaboration with Drs. James Thomson, Roger Pedersen, and John Gearhart, some of us at Geron Corporation launched a project to isolate these cells and grow them as stable cell lines. These cells, called human embryonic stem cells, were the first naturally immortal human cells ever isolated due to their abundant natural expression of telomerase. They had the wonderful property of being able to generate each and every cell type of the human body. For the first time in history, medicine had in its hands a pluripotent stem cell to make every cellular component of the human body. (Pluripotent stem cells are capable of differentiation into any other functional (somatic) cell the body needs.)

These cells generated considerable excitement since they were a means of mass-producing replacement cells for the treatment of a host of degenerative diseases involving the loss or dysfunction of cells, including those in osteoarthritis, macular degeneration, diabetes, heart failure, Parkinson’s disease, and numerous other disorders. The first report of the isolation of these cells marked the birth of the new field called regenerative medicine. When perfected, this technology offered the theoretical potential of rejuvenating an entire human body back to a youthful state.

Cloning – A Cellular Time Machine

In 1997, Dolly the sheep was cloned. The way cloning works is that the DNA of a somatic cell is transplanted into an egg (germ-line) cell, whose own DNA has been removed to create a pluripotent cell. This “cloned” cell is capable of differentiating into a new individual with the DNA from an existing individual.

Thus, cloning is an artificial means of generating identical twins differing in age. In the case of nuclear transfer, the DNA in the somatic cells is reprogrammed, meaning its memory of being a skin cell has been erased by a cellular “time machine”, and that cell has now been returned to the germ-line state capable again of making individuals of the same genetic constitution, over and over again…potentially forever!

But one may ask, in the case of cloning, what happens to the aging process of the body cell? Is aging of the cell really reversed, or do we somehow get an embryo and resulting cloned animal that looks young, but is really born old, a kind of “fountain of old age”? At first, the group that cloned Dolly reported that she was born with short telomeres, and cloning had not, reversed the aging process. Dolly was therefore thought to be “born old”; she was a sheep in lamb’s clothing, so to speak.

However, in 2000, our group published a paper demonstrating that, in the case of cow cloning, the telomere clock of cell aging is reset back to the beginning of life. Today, the consensus view is that cloning is capable of reversing cell aging, so animals cloned from aged animals are born young again. If you think about these results, they logically lead to the next question: Would cloning work in humans—not necessarily to make copies of them, but rather as means of reversing the aging of human cells?

Thus, cloning (somatic cell nuclear transfer) could potentially be used to reverse the developmental aging of a human cell. It became a topic of considerable controversy that, for example, a mature skin cell could possibly be transported back in time to the beginning of life. Some of us believe that such a cellular time machine could be used to make young cells of any kind that would be genetically identical to any given patient. This concept came to be called therapeutic cloning, in order to distinguish it from making a cloned human being (the latter process is referred to as reproductive cloning).

Induced Pluripotent Stem (iPS) Cells

Today, the controversy over therapeutic cloning has largely dissipated due to the discovery that the use of just a handful of molecules can effectively replace the use of a whole egg cell in restoring aged somatic cells back to pluripotency (youthful cells capable of differentiation into any other functional (somatic) cell.

In other words, we can take human somatic cells back to the embryonic germ-line state of immortal pluripotency without cloning or ever making an embryo. Since such cells are not isolated from embryos, they are called induced pluripotent stem (iPS) cells, in order to distinguish them from embryonic stem cells.

Most significantly, as reported in Life Extension magazine22 (Biotime’reversing cellular aging-DATE?), we demonstrated that it is possible to utilize these advances to not only revert a cell in the body back to the all-powerful pluripotent stem cell state, but also to activate telomerase and reset the clock of cell aging all the way back to the very beginning of life.

As a result, the stage is now set to lift some cell from the body—perhaps from a sliver of skin, from blood cells, or from a hair pulled from the head—and then genetically manipulate that cell, returning (converting) it to a continuously proliferating youthful line of cells. These rejuvenated cells we believe will be identical to the individual cell they had developed from decades earlier. Since these iPS cells are now reverted back to the germ-line state, they can spin off new somatic cells of all types for an indefinite period of time.

A thoughtful person would recognize within these advances the powerful means to potentially regenerate aged tissues with young cells, and a means to do so for periods that extend the normal lifespan of human body cells.

All of this new technology targets the upstream clockwork mechanisms of aging. This is possible because life is, in a sense, naturally immortal in that each species has cells capable of regenerating new individuals continuously and for an indefinite period of time.

Applying Regenerative Medicine to Heart Disease

In thinking about where such technologies could be applied, we first considered cardiovascular disease heart failure and stroke are the first and third-ranked causes of death in the United States.
Although epidemiological studies have demonstrated that abnormal lipid profile, diabetes, sedentary lifestyle, and genetic susceptibility are risk factors for coronary disease, hypertension, congestive heart failure, and stroke, advancing age is unequivocally the major risk factor for these diseases. Therefore, we seek a means to target the upstream mechanisms of vascular aging by replacing aged coronary artery cells with the young cells we were born with. This approach could become the most effective means of intervening in heart disease, stroke, and other cardiovascular diseases.

Life Extension’s contribution to this research

In late December 2010, I approached the Life Extension Foundation about the opportunity to accelerate the pace of research that could lead to the reversal of vascular aging using technologies described in this article. Recognizing the potential to cure the most common problem afflicting aging humans, Life Extension provided $2 million of initial funding.

These funds were used to help launch ReCyte Therapeutics, which is focused on regenerating aged vascular function by developing clinical applications based on several of the technologies we have been discussing. The mission is to reverse the developmental aging of a person’s cells and then turn those reprogrammed and rejuvenated cells into primitive vascular progenitors useful in “re-plumbing” an aged vascular system.

ReCyte’s scientists are particularly interested in a cellular component of blood vessels called endothelial cells that reside on the inner lining of the blood vessel. Normal endothelial function and endothelial health are adversely affected by the aging process, presumably due to telomere attrition (and other factors). An aged vasculature is therefore more prone to develop plaques, inflammation, and atherosclerosis. Therefore, myocardial infarction is really not the problem of the heart per se, but rather a problem with the vasculature’s supply of blood to the heart. The goal of ReCyte is to manufacture young vascular progenitor cells capable of repairing aged blood vessels, to target the upstream biology of the aging artery, not the downstream events of inflammation or cholesterol accumulation, arterial calcium deposits, and the formation of atherosclerotic plaques.

Where we are today?

With financial help from the Life Extension Foundation we have been able to improve the efficiency of reprogramming cells using technology licensed from the Wistar Institute in Philadelphia, Pennsylvania, with whom we now collaborate. Wistar scientists discovered that by turning off a gene called SP100, differentiated cells became more susceptible to re-expressing genes normally expressed only in pluripotent stem cells.

Second, we have formed a similar collaboration agreement with scientists at Cornell Weill College of Medicine in New York City who are focused on the development of vascular endothelium. In collaboration with that group, we have successfully generated purified populations of embryonic vascular cells from induced pluripotent stem cells.

As a result, we believe the pieces are in place to reverse the developmental aging of an aged person’s cells and then to turn these rejuvenated pluripotent stem cells into young vascular progenitors that should be useful in restoring normal youthful function to the aged vasculature of the heart, brain, and other tissues. Such cells would also be histocompatible with individual patients, which means there would be no need for immunosuppressive drugs. We have already derived these endothelial cells from multiple human embryonic cell lines at clinically applicable scale consistent with Good Manufacturing Practice (GMP).

In summary, at the same moment when we see an aging population placing a strain on our healthcare system and our national budget, we also see the rise of a new technology facilitating the manufacture, on a clinically-feasible scale, of young cells of all types that may allow us to regenerate tissues afflicted with age-related degenerative disease.

STEM CELL PIONEERS AWARDED NOBEL PRIZE

sOn October 9, 2012, two scientists who helped lay the foundation for regenerative medicine were awarded the Nobel Prize in Physiology or medicine.

The shared nobel Prize was given to Dr. John b. gurdon of the university of cambridge in england and Dr. Shinya yamanaka of kyoto university in Japan for their work on induced pluripotent stem cells (iPS).27

In granting the award, the Nobel Prize Assembly stated:

“Research during recent years has shown that iPS cells can give rise to all the different cell types of the body....and led to remarkable progress in many areas of medicine. for instance, skin cells can be obtained from patients with various diseases, reprogrammed, and examined in the laboratory to determine how they differ from cells of healthy individuals. Such cells constitute invaluable tools for understanding disease mechanisms and so provide new opportunities to develop medical therapies.”

About BioTime

At BioTime we are utilizing these breakthroughs in regenerative medicine to target several major diseases. BioTime can be thought of as the hub of a wheel with several subsidiaries focused on different medical specialties such as orthopedics, cardiovascular disease, neuroscience, and so on. Recyte Therapeutics is one of those subsidiaries.

BioTime (NYSE MKT: BTX), both as a company and as individuals, are determined to find the means of rapidly translating this bench-top science into life-saving clinical reality. We are thankful for the support of the Life Extension Foundation for their vision and commitment to advancing human health. We look forward to the day when we can report in Life Extension magazine, the outcomes of the first patients to be treated with reprogrammed young vascular progenitor cells as a novel therapy for cardiovascular disease, the number one cause of mortality in aging humans.

Summary

Very early in the course of human development, a small cluster of cells form, each of which has the power to become any of the cell types in the human body. Cells that have this power are said to be pluripotent, meaning they have power (-potent) to become a variety (plurality or pluri-) of cell types. These cells commit to the cell type they will eventually become, that is, each cell will commit to becoming a reproductive (sperm or egg) cell, or one of the body’s many somatic or life-functioning cell types such as muscle, blood, or brain cells. If pluripotent cells differentiate into sperm or egg cells, they are remaining in the germ-line, that lineage of cells that connects the generations and is the biological basis of the immortality of the species. When cells make the decision to become somatic, they turn off telomerase, an enzyme that synthesizes a repeated sequence of DNA over and over again at the end of DNA strands needed to maintain cellular viability.9-12 A recent discovery showed that the use of just a handful of molecules can effectively restore aged somatic cells back to pluripotency. It is possible to utilize these advances to not only revert a cell in the body back to the all-powerful pluripotent stem cell state, but also to activate telomerase and reset the clock of cell aging all the way back to the very beginning of life.

If you have any questions on the scientific content of this article, please call a Life Extension® Health Advisor at 1-866-864-3027.

References

1. Chung HY, Sung B, Jung KJ, Zou Y, Yu BP. The molecular inflammatory process in aging. Antioxid Redox Signal. 2006 Mar- Apr;8(3-4):572-81.

2. Bartsch H, Nair J. Chronic inflammation and oxidative stress in the genesis and perpetuation of cancer: role of lipid peroxidation, DNA damage, and repair. Langenbecks Arch Surg. 2006 Sep;391(5):499-510.

3. Lavrovsky Y, Chatterjee B, Clark RA, Roy AK. Role of redox-regulated transcription factors in inflammation, aging and age-related diseases. Exp Gerontol. 2000 Aug;35(5):521-32.

4. Brüünsgaard H, Pedersen BK. Age-related inflammatory cytokines and disease. Immunol Allergy Clin North Am. 2003 Feb;23(1):15-39.

5. Chung HY, Cesari M, Anton S, et al. Molecular inflammation: underpinnings of aging and age-related diseases. Ageing Res Rev. 2009 Jan;8(1):18-30.

6. Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation. 2002 Mar 5;105(9):1135-43.

7. DaneshJ, Whincup P, Walker M, et al. Low grade inflammation and coronary heart disease: prospective study and updated metaanalyses. BMJ. 2000 321:199–204.

8. Kofler S, Nickel T, Weis M. Role of cytokines in cardiovascular diseases: a focus on endothelial responses to inflammation. Clin Sci (Lond). 2005 Mar;108(3):205-13.

9. Harley CB. Telomere loss: mitotic clock or genetic time bomb? Mutat Res. 1991 Mar-Nov;256(2-6):271-82.

10. Bekaert S, Derradji H, Baatout S. Telomere biology in mammalian germ cells and during development. Dev Biol. 2004 Oct 1;274(1):15-30.

11. Gourronc FA, Klingelhutz AJ. Therapeutic opportunities: telomere maintenance in inducible pluripotent stem cells. Mutat Res. 2012 Feb 1;730(1-2):98-105.

12. Herbert B-S, Pitts AE, Baker SI, et al. Inhibition of human telomerase in immortal human cells leads to progressive telomere shortening and cell death. Proc. Natl. Acad. Sci. USA. 1999 96:14726-14781.

13. Cawthon RM, Smith KR, O’Brien E, Sivatchenko A, Kerber RA. Association between telomere length in blood and mortality in people aged 60 years or older. Lancet. 2003 Feb 1;361(9355):393-5.

14. Willeit P, Willeit J, Mayr A, et al. Telomere length and risk of incident cancer and cancer mortality. JAMA. 2010 Jul 7;304(1):69-75. 15. Ding H, Chen C, Shaffer JR, et al. Telomere length and risk of stroke in Chinese. Stroke. 2012 Mar;43(3):658-63.

15. Ding H, Chen C, Shaffer JR, et al. Telomere length and risk of stroke in Chinese. Stroke. 2012 Mar;43(3):658-63.

16. Weischer M, Bojesen SE, Cawthon RM, Freiberg JJ, Tybjærg- Hansen A, Nordestgaard BG. Short telomere length, myocardial infarction, ischemic heart disease, and early death. Arterioscler Thromb Vasc Biol. 2012 Mar;32(3):822-9.

17. Valdes AM, Andrew T, Gardner JP, et al. Obesity, cigarette smoking, and telomere length in women. Lancet. 2005 Aug 20- 26;366(9486):662-4.

18. McGrath M, Wong JY, Michaud D, Hunter DJ, De Vivo I. Telomere length, cigarette smoking, and bladder cancer risk in men and women. Cancer Epidemiol Biomarkers Prev. 2007 Apr;16(4):815-9.

19. Kiecolt-Glaser JK, Epel ES, Belury MA, et al. Omega-3 fatty acids, oxidative stress, and leukocyte telomere length: A randomized< controlled trial. Brain Behav Immun. 2012 Sep 23.

20. Stadtfeld M, Hochedlinger K. Induced pluripotency: history, mechanisms, and applications. Genes Dev. 2010 Oct 15;24(20):2239-63.

21. Lanza RP, Cibelli JB, Blackwell C, et al. Extension of cell life-span and telomere length in animals cloned from senescent somatic cells. Science. 2000 Apr 28;288(5466):665-9.

22. Available at: http://www.lef.org/magazine/mag2010/jun2010_Immortal-Stem-Cells-for-Anti-Aging-Therapies_01.htm?source=search&key=biotime. Accessed October 11, 2012.

23. Erusalimsky JD, Skene C. Mechanisms of endothelial senescence. Exp Physiol. 2009 Mar;94(3):299-304. 24. Voghel G, Thorin-Trescases N, Mamarbachi AM, et al. Endogenous oxidative stress prevents telomerase-dependent immortalization of human endothelial cells. Mech Ageing. Dev. 2010 May;131(5):354-63.

25. Satoh M, Ishikawa Y, Takahashi Y, Itoh T, Minami Y, Nakamura M. Association between oxidative DNA damage and telomere shortening in circulating endothelial progenitor cells obtained from metabolic syndrome patients with coronary artery disease. Atherosclerosis. 2008 Jun;198(2):347-53.

26. Samani NJ, Boultby R, Butler R, Thompson JR, Goodall AH. Telomere shortening in atherosclerosis. Lancet. 2001 Aug 11;358(9280):472-3. 27. Available at: http://www.guardian.co.uk/science/blog/2012/oct/08/nobel-prize-2012-live-medicine-physiology. Accessed October 11, 2012 28. Available at: http://www.genengnews.com/gen-news-highlights/biotime-licenses-technology-for-gene-underlying-cancer-and-stemcell-reprogramming/81246259/. Accessed October 11, 2012. 29. West MD, Vaziri H. Back to Immortality: The restoration of embryonic telomere length during induced pluripotency. Regen Med. 2010;5(4):485-8.

Regenerative Medicine 2
Molecular Brain Switch

Flip of a single molecular switch makes an old brain young
By Bill Hathaway
March 6, 2013



A cultured neuron with projecting dendrites studded with sites of communication between neurons, known as dendritic spines.

The flip of a single molecular switch helps create the mature neuronal connections that allow the brain to bridge the gap between adolescent impressionability and adult stability. Now Yale School of Medicine researchers have reversed the process, recreating a youthful brain that facilitated both learning and healing in the adult mouse.

Scientists have long known that the young and old brains are very different. Adolescent brains are more malleable or plastic, which allows them to learn languages more quickly than adults and speeds recovery from brain injuries. The comparative rigidity of the adult brain results in part from the function of a single gene that slows the rapid change in synaptic connections between neurons.

By monitoring the synapses in living mice over weeks and months, Yale researchers have identified the key genetic switch for brain maturation a study released March 6 in the journal Neuron. The Nogo Receptor 1 gene is required to suppress high levels of plasticity in the adolescent brain and create the relatively quiescent levels of plasticity in adulthood. In mice without this gene, juvenile levels of brain plasticity persist throughout adulthood. When researchers blocked the function of this gene in old mice, they reset the old brain to adolescent levels of plasticity.

“These are the molecules the brain needs for the transition from adolescence to adulthood,” said Dr. Stephen Strittmatter. Vincent Coates Professor of Neurology, Professor of Neurobiology and senior author of the paper. “It suggests we can turn back the clock in the adult brain and recover from trauma the way kids recover.”



A 3-D reconstruction of neurons in the somatosensory cortex

Rehabilitation after brain injuries like strokes requires that patients re-learn tasks such as moving a hand. Researchers found that adult mice lacking Nogo Receptor recovered from injury as quickly as adolescent mice and mastered new, complex motor tasks more quickly than adults with the receptor.

“This raises the potential that manipulating Nogo Receptor in humans might accelerate and magnify rehabilitation after brain injuries like strokes,” said Feras Akbik, Yale doctoral student who is first author of the study.

Researchers also showed that Nogo Receptor slows loss of memories. Mice without Nogo receptor lost stressful memories more quickly, suggesting that manipulating the receptor could help treat post-traumatic stress disorder.

“We know a lot about the early development of the brain,” Strittmatter said, “But we know amazingly little about what happens in the brain during late adolescence.”

Other Yale authors are: Sarah M. Bhagat, Pujan R. Patel and William B.J. Cafferty

The study was funded by the National Institutes of Health. Strittmatter is scientific founder of Axerion Therapeutics, which is investigating applications of Nogo research to repair spinal cord damage.

http://news.yale.edu/2013/03/06/flip-single-molecular-switch-makes-old-brain-young

Regenerative Medicine 4

Companies Doing
Tissue Repair and Organ Grow
By Joseph Cafariello
February 21, 2013

Wolverine—comic book hero and one of the central characters of the movie box-office smash-hit trilogy “X-Men”—is a mutant with unique abilities. One of them is to spontaneously heal himself from cuts and wounds simply by growing new cells and repairing his damaged flesh.

Ah, what one would do with that ability? Trying your hand at bullfighting? No problem. Snorkeling in shark infested waters? No fears there. Challenged to a sword duel? Bring it on. Nothing can stop you now.

Well, the marvels of medical science may very well have taken the human species one step closer to self-regeneration without requiring us to become mutants.

Yet at the cellular level, humans—and all life forms, for that matter—already have the ability to repair damaged cells and tissue. Even serious injuries sustained from major accidents can be naturally repaired over time.

What regenerative medicine is attempting to do is simply boost the body’s natural healing processes into overdrive. Wikipedia defines the endeavor:

“This field holds the promise of regenerating damaged tissues and organs in the body by replacing damaged tissue and/or by stimulating the body's own repair mechanisms to heal previously irreparable tissues or organs. Regenerative medicine also empowers scientists to grow tissues and organs in the laboratory and safely implant them when the body cannot heal itself.”

Numerous companies have been on the scene for years exploring ways to advance the science—and business—of regenerative medicine. And they are getting closer and closer to delivering results.

One company to watch in this field is Shire PLC (LON: SHP, NASDAQ: SHPG) which has a long pipeline of medicines and treatments at various phases of clinical trials across three main areas of medical treatment: specialty trauma, human genetic therapies, and regenerative medicine.

Shire recently “announced the initiation of a Phase 3 study designed to evaluate the efficacy and safety of ABH001, its dermal substitute therapy, for the treatment of non-healing wounds in patients with Epidermolysis Bullosa (EB), a group of rare genetic skin disorders”. ABH001 has now received an orphan drug designation by; the U.S. and European Union, as well as, the U.S. Food and Drug Administration’s Fast Track designation.

Regenerative medicine is also attempting to use the body’s own stem cells to repair or even manufacture new body parts, which are considered safer than organs received from donors.

Two firms in the area of stem cell research are the aptly named StemCells, Inc. (NASDAQ: STEM) and Athersys, Inc. (NASDAQ: ATHX).

Stem Cells Inc. recently announced that 12-month data from the first patient cohort in the Newark, California-based company’s Phase I/II clinical trial of its proprietary HuCNS-SC® product candidate for chronic spinal cord injury continued to demonstrate a favorable safety profile.”

Two other patients in the trial “retained gains in sensory function at the one-year mark that were demonstrated at a six-month assessment. One patient even converted from a ‘complete’ to an ‘incomplete’ injury and the third patient remains stable.”

Martin McGlynn, President and Chief Executive at Stem Cells—though drawing attention to the small number of patients participating in the uncontrolled trial—was nonetheless very optimistic, announcing that “this is the first time a patient with a complete spinal cord injury has been converted to a patient with an incomplete injury following transplantation of neural stem cells.”

Athersys Inc. describes its flagship product candidate called MultiStem:

“We are developing a patented and proprietary non-embryonic stem cell therapy called MultiStem for the treatment of cardiovascular disease, neurological conditions, and inflammatory and immune conditions, as well as certain other potential applications.

“Over the past several years, we have advanced multiple programs into clinical development, and currently have four clinical stage programs involving MultiStem. These programs are exploring the potential use of MultiStem to treat:

• Inflammatory Bowel Disease (part of an ongoing Phase 2 clinical trial being conducted in partnership with Pfizer)

• Ischemic stroke (ongoing Phase 2 clinical trial)

• Complications associated with traditional bone marrow or hematopoietic stem cell transplants, such as Graft Versus Host Disease (GVHD) (recently completed Phase1 clinical trial - Orphan Drug designation)

• Damage from acute myocardial infarction (i.e. heart attack)”


With all this research and development into regenerative medicine garnering increasingly more attention and funding from the investment community, the Wolverine who leapt out of the comic books and onto the silver screen may be getting closer to taking yet another giant leap—into real life.

The Molecular Repair of the Brain

The following link to the discussion and research source material is advanced reading for these seeking an extensive discussion.

The Molecular Repair of the Brain which discusses repair technologies that are clearly feasible in principle. http://www.merkle.com/cryo/techFeas.html Also see: Cryo-probability which discusses the chances of success http://merkle.com/cryo/probability.html