Courtesy of Life Extension magazine
LE Magazine November 2008
Regenerative Medicine Breakthroughs
Will BioTime Reset the Clock of Aging?
By Julius Goepp, MD
Regenerative Medicine Breakthroughs
Rapid advances in the field of stem cell therapeutics are bringing us closer to the elusive goal of harnessing the ?immortal flame? that survives in all of us. Indeed, it has become clear that, in the words of internationally known gerontology researcher Dr. Michael West, ?You and I are made from cells that have no dead ancestors.?
Life Extension interviewed Dr. West recently, to learn about his paradigm-shattering work, which has led to new techniques related to induced pluripotent stem cells (iPS) and human embryonic progenitor cells (hEP), both of which allow researchers to leap-frog over many previously existing barriers. Shortly after our interview, Harvard researchers announced that they had used the iPS technique to produce a ?robust new collection of disease-specific stem cell lines? that hold immediate hope for advances in a host of diseases including Parkinson?s disease, type 1 diabetes, Huntington?s disease, Down?s syndrome, a form of combined immunodeficiency (?bubble boy disease?), two forms of muscular dystrophy, and others.1
Based on our discussion with Dr. West, combined with the recent news from the Harvard researchers, it appears that we are truly poised at the threshold of an incredible new era in which scientists can unlock the inner workings of our cells and ?mass produce? virtually any cell or tissue type in the human body in a youthful state.
The implications of these advances are enormous. They include readily accessible tissue and organ transplantation, the obliteration of genetic disorders, the end of chronic age-related diseases, and perhaps even physical immortality itself.
Some Background
?We?re seeing a congruence between some of mankind?s oldest aspirations and where modern science is heading,? West begins. ?From ancient times, we?ve recognized that, although we as individuals age and die, the species does not. Amazing as it sounds, each of us is made of cells that have been proliferating since the dawn of life on Earth. And that, really, was the beginning of what we today seek to achieve through gerontology and regenerative medicine.?
The lineage of cells produced by the reproductive system has been known as ?germ-line? cells since the work of 19th century German scientist August Weismann. West continues, ?Weismann recognized that germ-line cells represent a lineage of cells that has continued unbroken since life began?these cells obviously never aged or you and I would not be here.?
Weismann was interested in this fundamental question: why is it that the non-germ-line cells in our bodies (the somatic cells) inevitably age and die on cue. As West asks, ?Why are cells in our skin, our blood, our bones, and even our brains so reproducibly programmed to age in such a short period of time, while germ-line cells have been proliferating for billions of years??
Intrigued, Weismann made an astonishing prediction in 1881, speculating that the reason individuals age is that somatic cells (what we are mostly made of) have somehow lost the capacity (still inherent in primitive single-celled creatures) for proliferating without limit. Restore that capability, Weismann claimed, and one would restore the cellular immortality still present in our germ-line cells.
A series of elegant and now classic experiments by the biologist Leonard Hayflick in the 1950s showed, in fact, that there is a limit to how many times human somatic cells can reproduce in vitro before they simply stop. Hayflick had discovered the existence of what amounts to a cellular ?clock? that appears to run down after a relatively short number of generations of cell replication.
Telomeres: Cellular Fuses
What is the actual physical nature of the mysterious ?cellular clock? that limits the life span of human somatic cells?
Telomeres: Cellular Fuses
Primitive embryonic cells that are stained to show the nuclei containing the DNA.
At the time when Dr. West began his scientific career, he became convinced that this intrinsic clock of cellular aging was somehow connected with the chromosomes. He became intrigued by a little-known theory proposed in the early 1970s by Russian scientist Alexy Olovnikov.2,3 ?Olovnikov?s idea was that repeating DNA sequences at the ends of each chromosome were like a burning fuse, which acted as a clock because every time the cell replicated, the segment (called a telomere) became shorter and shorter. When it ?ran out,? the cellular machinery signaled a fatal error in copying the vital genetic material, which would trigger the senescence of the somatic cell.? The full-length repeating telomere sequence was maintained in germ-line cells, Olovnikov suggested, by an ?immortalizing enzyme? that continuously spun fresh telomere DNA, allowing germ-line cells to reproduce forever.4
By 1986, West had read the work of biologist Howard Cook who found that telomeres shortened with each generation in white blood cells (which are somatic cells and have finite life spans), but maintained their length in germ-line cells like sperm.
Seeing these puzzle pieces fall into place was so convincing that West took a leave of absence from medical school to court venture capitalists, eventually starting a company called Geron to build on what West still refers to as the ?telomere gamble.? ?Forty million dollars later,? West recalls, ?the gamble paid off.? West?s group had in fact produced Olovnikov?s mysterious enzyme, now known as telomerase, because of its ability to continuously spin out the vital strands of telomere DNA that keep germ cells immortal.
Immortalized Cells: Can They Lengthen Individual Life Spans?
But would it work? Could Dr. West actually convert human somatic cells, destined to expire after a few score doublings in tissue culture, into immortal versions of themselves that could continue to grow normally? In a fitting tribute, West chose to collect actual skin cells from pioneer Leonard Hayflick and insert the telomerase gene into them. In a notebook headed ?The Immortalization of Dr. Hayflick,? Dr. West recorded the astonishing findings: Hayflick?s untreated skin cells began to die off after about two months in culture, exactly as expected, but cells that had been infused with the telomerase gene continued to thrive in identical culture conditions! These ?telomerized? human somatic cells had demonstrated scientists? ability to ?rewind? the clock of cellular aging.5
While the immortalization of cells was a giant leap forward, says Dr. West, it wasn?t clear what role the telomere and the telomerase enzyme played in aging at the level of a human individual.
There were several intriguing directions to go in at this point. It?s now known, for example, that telomere length is related to the risk of many chronic diseases.6-12 What about simply finding a way to restore the telomerase gene to every somatic cell in the body, lengthening all the telomeres together?wouldn?t that result in a body with an essentially limitless supply of cells?
?That?s exactly how I was thinking back in the mid-90s,? West responds. ?Why not just package the telomerase gene up in a virus? (Viruses provide a common laboratory method of introducing specific genes into cells.) Although gene therapy hadn?t come of age at that point, it seemed that if we took that approach and succeeded, it could have a profound impact on aging.
Embryonic Stem Cells and Cloning
Embryonic Stem Cells and Cloning
BioTime scientist captures information on the molecular properties of new primitive cell types.
But gene transfer using viruses was a tricky business fraught with pitfalls, especially in the 1990s. In a dramatic conceptual leap, Dr. West suggested an alternative: why not go all the way back to embryonic stem cells, which are formed immediately after a sperm fertilizes an egg? For the first several cell division cycles, all cells are identical, and capable of differentiating into every cell type in the body (in fact, so-called ?identical twins? are the result of a two-cell embryo splitting apart, producing an entirely new individual from each primitive embryonic stem cell).
?If we could immortalize embryonic stem cells,? West says, ?we could potentially repair the human heart, for example, after a heart attack, making young heart muscle by injecting these primitive cells into the heart to regenerate damaged tissue.? That was an astonishingly prescient vision because we?re already seeing clinical trials using this technique (cardiomyoplasty) in humans.13
In 1998, West reasoned that if an aged somatic cell were returned to the germ line, such as is used in cloning, it might be possible to not only reprogram say a skin cell into embryonic stem cells, but also reset the clock of aging in the aged cell. In 1999, the team that cloned Dolly the sheep had reported that cloning did not in fact do this, that is, they reported that Dolly was born old because the egg cell could not reset telomere length.14 However, Dr. West?s group later demonstrated that the Dolly team had it wrong, and that cloning could reset the clock of aging in animal cells after all.15
This suggested that there may actually be a way to use germ-line cells like the egg cell as a cellular time machine, resetting the clock of aging in human cells, turning a skin cell into the primitive embryonic stem cells we were originally developed from and creating young cells and tissues of any kind to repair the ravages of aging.
Of course, cloning and the use of human embryonic stem cells are highly controversial, to say the least. The situation has been made worse by extreme political posturing on the one hand,16,17 and instances of overt scientific fraud on the other.18-21 These procedures are also technically challenging.
What You Need to Know: Regenerative Medicine Breakthroughs
*
Stem cell therapy has tremendous potentialfor the development of medical applications to repair and regenerate diseased, injured, and aging organs and tissues. Stem cell therapy may even be able to turn back the clock of cellular aging and promote radical life extension.
*
At the forefront of this exciting new field is gerontologist Dr. Michael West, CEO of BioTime, Inc.
*
While somatic cells in the body age and die, germ-line cells have been proliferating for billions of years.
*
The shortening of telomeres is linked with cellular aging, and telomere length is related to the risk of numerous diseases.
*
Germ cells possess an enzyme called telomerase that allows them to maintain the length of their telomeres and reproduce forever. Introducing the telomerase gene into somatic cells increases their longevity.
*
Dr. West has proposed that embryonic stem cells may offer tremendous therapeutic promise; however, the use of human embryonic stem cells derived from human embryos is highly controversial.
*
Introducing transcription factors from egg cells to somatic cells can cause them to be transformed into embryonic stem cells that can be developed into every different cell type in the body.
*
Studies show that induced pluripotent stem cells demonstrate an activated telomerase gene, which maintains the length of telomeres. This could be the first step in reversing cellular aging in humans.
*
Embryonic progenitor cells are capable of developing into many cells of a particular tissue type, such as blood or nervous system cells. When injected into injured or aged tissue, they could develop into healthy appropriate cell types.
*
Recent studies show that stem cell therapy holds promise in managing nervous system disorders, musculoskeletal conditions, ischemic stroke, brain tumors, and more.
Beyond Cloning: At the Threshold of Modern Regenerative Medicine
Beyond Cloning: At the Threshold of Modern Regenerative Medicine
A microscopic view of neural crest cells that have the potential to make for the first time the cells of the human face.
?But the really good news,? Dr. West says with obvious excitement, ?is that a team at Kyoto University in Japan has now shown that it?s possible to take some molecules, called transcription factors, out of the egg cell, and use them to act just like the egg cell itself in transforming an ordinary somatic cell, say from the skin, and taking it back in time to become an embryonic stem cell!?
No need for cloning and then deriving stem cells from the cloned embryo?or any of the challenging and controversial techniques that have preoccupied the media for the past decade. ?The new cells are called induced pluripotent stem cells (iPS),? West explains. ?They are equivalent in function to embryonic stem cells, but they don?t come from an embryo?hence the name change. The idea is simple: take a skin cell, culture it in a dish, add in three or four of these transcription factors, and, over a couple of weeks, the skin cells are transformed back into colonies of stem cells that act exactly like embryonic stem cells.22-24 It?s just spectacular, really.?
?And since numerous papers on iPS have now shown switching on the telomerase gene in these cells,? continues Dr. West, ?I believe that within the next 12 months, the scientific community will have documented, for the first time ever, the reversal of aging of a human cell.?
LE Magazine November 2008
Regenerative Medicine Breakthroughs
Will BioTime Reset the Clock of Aging?
By Julius Goepp, MD
Regenerative Medicine Breakthroughs
Rapid advances in the field of stem cell therapeutics are bringing us closer to the elusive goal of harnessing the ?immortal flame? that survives in all of us. Indeed, it has become clear that, in the words of internationally known gerontology researcher Dr. Michael West, ?You and I are made from cells that have no dead ancestors.?
Life Extension interviewed Dr. West recently, to learn about his paradigm-shattering work, which has led to new techniques related to induced pluripotent stem cells (iPS) and human embryonic progenitor cells (hEP), both of which allow researchers to leap-frog over many previously existing barriers. Shortly after our interview, Harvard researchers announced that they had used the iPS technique to produce a ?robust new collection of disease-specific stem cell lines? that hold immediate hope for advances in a host of diseases including Parkinson?s disease, type 1 diabetes, Huntington?s disease, Down?s syndrome, a form of combined immunodeficiency (?bubble boy disease?), two forms of muscular dystrophy, and others.1
Based on our discussion with Dr. West, combined with the recent news from the Harvard researchers, it appears that we are truly poised at the threshold of an incredible new era in which scientists can unlock the inner workings of our cells and ?mass produce? virtually any cell or tissue type in the human body in a youthful state.
The implications of these advances are enormous. They include readily accessible tissue and organ transplantation, the obliteration of genetic disorders, the end of chronic age-related diseases, and perhaps even physical immortality itself.
Some Background
?We?re seeing a congruence between some of mankind?s oldest aspirations and where modern science is heading,? West begins. ?From ancient times, we?ve recognized that, although we as individuals age and die, the species does not. Amazing as it sounds, each of us is made of cells that have been proliferating since the dawn of life on Earth. And that, really, was the beginning of what we today seek to achieve through gerontology and regenerative medicine.?
The lineage of cells produced by the reproductive system has been known as ?germ-line? cells since the work of 19th century German scientist August Weismann. West continues, ?Weismann recognized that germ-line cells represent a lineage of cells that has continued unbroken since life began?these cells obviously never aged or you and I would not be here.?
Weismann was interested in this fundamental question: why is it that the non-germ-line cells in our bodies (the somatic cells) inevitably age and die on cue. As West asks, ?Why are cells in our skin, our blood, our bones, and even our brains so reproducibly programmed to age in such a short period of time, while germ-line cells have been proliferating for billions of years??
Intrigued, Weismann made an astonishing prediction in 1881, speculating that the reason individuals age is that somatic cells (what we are mostly made of) have somehow lost the capacity (still inherent in primitive single-celled creatures) for proliferating without limit. Restore that capability, Weismann claimed, and one would restore the cellular immortality still present in our germ-line cells.
A series of elegant and now classic experiments by the biologist Leonard Hayflick in the 1950s showed, in fact, that there is a limit to how many times human somatic cells can reproduce in vitro before they simply stop. Hayflick had discovered the existence of what amounts to a cellular ?clock? that appears to run down after a relatively short number of generations of cell replication.
Telomeres: Cellular Fuses
What is the actual physical nature of the mysterious ?cellular clock? that limits the life span of human somatic cells?
Telomeres: Cellular Fuses
Primitive embryonic cells that are stained to show the nuclei containing the DNA.
At the time when Dr. West began his scientific career, he became convinced that this intrinsic clock of cellular aging was somehow connected with the chromosomes. He became intrigued by a little-known theory proposed in the early 1970s by Russian scientist Alexy Olovnikov.2,3 ?Olovnikov?s idea was that repeating DNA sequences at the ends of each chromosome were like a burning fuse, which acted as a clock because every time the cell replicated, the segment (called a telomere) became shorter and shorter. When it ?ran out,? the cellular machinery signaled a fatal error in copying the vital genetic material, which would trigger the senescence of the somatic cell.? The full-length repeating telomere sequence was maintained in germ-line cells, Olovnikov suggested, by an ?immortalizing enzyme? that continuously spun fresh telomere DNA, allowing germ-line cells to reproduce forever.4
By 1986, West had read the work of biologist Howard Cook who found that telomeres shortened with each generation in white blood cells (which are somatic cells and have finite life spans), but maintained their length in germ-line cells like sperm.
Seeing these puzzle pieces fall into place was so convincing that West took a leave of absence from medical school to court venture capitalists, eventually starting a company called Geron to build on what West still refers to as the ?telomere gamble.? ?Forty million dollars later,? West recalls, ?the gamble paid off.? West?s group had in fact produced Olovnikov?s mysterious enzyme, now known as telomerase, because of its ability to continuously spin out the vital strands of telomere DNA that keep germ cells immortal.
Immortalized Cells: Can They Lengthen Individual Life Spans?
But would it work? Could Dr. West actually convert human somatic cells, destined to expire after a few score doublings in tissue culture, into immortal versions of themselves that could continue to grow normally? In a fitting tribute, West chose to collect actual skin cells from pioneer Leonard Hayflick and insert the telomerase gene into them. In a notebook headed ?The Immortalization of Dr. Hayflick,? Dr. West recorded the astonishing findings: Hayflick?s untreated skin cells began to die off after about two months in culture, exactly as expected, but cells that had been infused with the telomerase gene continued to thrive in identical culture conditions! These ?telomerized? human somatic cells had demonstrated scientists? ability to ?rewind? the clock of cellular aging.5
While the immortalization of cells was a giant leap forward, says Dr. West, it wasn?t clear what role the telomere and the telomerase enzyme played in aging at the level of a human individual.
There were several intriguing directions to go in at this point. It?s now known, for example, that telomere length is related to the risk of many chronic diseases.6-12 What about simply finding a way to restore the telomerase gene to every somatic cell in the body, lengthening all the telomeres together?wouldn?t that result in a body with an essentially limitless supply of cells?
?That?s exactly how I was thinking back in the mid-90s,? West responds. ?Why not just package the telomerase gene up in a virus? (Viruses provide a common laboratory method of introducing specific genes into cells.) Although gene therapy hadn?t come of age at that point, it seemed that if we took that approach and succeeded, it could have a profound impact on aging.
Embryonic Stem Cells and Cloning
Embryonic Stem Cells and Cloning
BioTime scientist captures information on the molecular properties of new primitive cell types.
But gene transfer using viruses was a tricky business fraught with pitfalls, especially in the 1990s. In a dramatic conceptual leap, Dr. West suggested an alternative: why not go all the way back to embryonic stem cells, which are formed immediately after a sperm fertilizes an egg? For the first several cell division cycles, all cells are identical, and capable of differentiating into every cell type in the body (in fact, so-called ?identical twins? are the result of a two-cell embryo splitting apart, producing an entirely new individual from each primitive embryonic stem cell).
?If we could immortalize embryonic stem cells,? West says, ?we could potentially repair the human heart, for example, after a heart attack, making young heart muscle by injecting these primitive cells into the heart to regenerate damaged tissue.? That was an astonishingly prescient vision because we?re already seeing clinical trials using this technique (cardiomyoplasty) in humans.13
In 1998, West reasoned that if an aged somatic cell were returned to the germ line, such as is used in cloning, it might be possible to not only reprogram say a skin cell into embryonic stem cells, but also reset the clock of aging in the aged cell. In 1999, the team that cloned Dolly the sheep had reported that cloning did not in fact do this, that is, they reported that Dolly was born old because the egg cell could not reset telomere length.14 However, Dr. West?s group later demonstrated that the Dolly team had it wrong, and that cloning could reset the clock of aging in animal cells after all.15
This suggested that there may actually be a way to use germ-line cells like the egg cell as a cellular time machine, resetting the clock of aging in human cells, turning a skin cell into the primitive embryonic stem cells we were originally developed from and creating young cells and tissues of any kind to repair the ravages of aging.
Of course, cloning and the use of human embryonic stem cells are highly controversial, to say the least. The situation has been made worse by extreme political posturing on the one hand,16,17 and instances of overt scientific fraud on the other.18-21 These procedures are also technically challenging.
What You Need to Know: Regenerative Medicine Breakthroughs
*
Stem cell therapy has tremendous potentialfor the development of medical applications to repair and regenerate diseased, injured, and aging organs and tissues. Stem cell therapy may even be able to turn back the clock of cellular aging and promote radical life extension.
*
At the forefront of this exciting new field is gerontologist Dr. Michael West, CEO of BioTime, Inc.
*
While somatic cells in the body age and die, germ-line cells have been proliferating for billions of years.
*
The shortening of telomeres is linked with cellular aging, and telomere length is related to the risk of numerous diseases.
*
Germ cells possess an enzyme called telomerase that allows them to maintain the length of their telomeres and reproduce forever. Introducing the telomerase gene into somatic cells increases their longevity.
*
Dr. West has proposed that embryonic stem cells may offer tremendous therapeutic promise; however, the use of human embryonic stem cells derived from human embryos is highly controversial.
*
Introducing transcription factors from egg cells to somatic cells can cause them to be transformed into embryonic stem cells that can be developed into every different cell type in the body.
*
Studies show that induced pluripotent stem cells demonstrate an activated telomerase gene, which maintains the length of telomeres. This could be the first step in reversing cellular aging in humans.
*
Embryonic progenitor cells are capable of developing into many cells of a particular tissue type, such as blood or nervous system cells. When injected into injured or aged tissue, they could develop into healthy appropriate cell types.
*
Recent studies show that stem cell therapy holds promise in managing nervous system disorders, musculoskeletal conditions, ischemic stroke, brain tumors, and more.
Beyond Cloning: At the Threshold of Modern Regenerative Medicine
Beyond Cloning: At the Threshold of Modern Regenerative Medicine
A microscopic view of neural crest cells that have the potential to make for the first time the cells of the human face.
?But the really good news,? Dr. West says with obvious excitement, ?is that a team at Kyoto University in Japan has now shown that it?s possible to take some molecules, called transcription factors, out of the egg cell, and use them to act just like the egg cell itself in transforming an ordinary somatic cell, say from the skin, and taking it back in time to become an embryonic stem cell!?
No need for cloning and then deriving stem cells from the cloned embryo?or any of the challenging and controversial techniques that have preoccupied the media for the past decade. ?The new cells are called induced pluripotent stem cells (iPS),? West explains. ?They are equivalent in function to embryonic stem cells, but they don?t come from an embryo?hence the name change. The idea is simple: take a skin cell, culture it in a dish, add in three or four of these transcription factors, and, over a couple of weeks, the skin cells are transformed back into colonies of stem cells that act exactly like embryonic stem cells.22-24 It?s just spectacular, really.?
?And since numerous papers on iPS have now shown switching on the telomerase gene in these cells,? continues Dr. West, ?I believe that within the next 12 months, the scientific community will have documented, for the first time ever, the reversal of aging of a human cell.?