by Michael D. West, Ph.D.
November 15, 2011
"Rare is the union of beauty and purity"
Juvenal
The confluence of supply and demand is the engine of commerce. Today, the aging U.S. baby boom population is creating one of the fastest growing sectors for new product demand in our history. This 76 million-person strong segment of our population is facing a surge of degenerative diseases, many having no known cure. Examples would be Parkinson’s disease, osteoarthritis, heart failure, macular degeneration, and so on. On the supply side of the equation is the emerging field called “regenerative medicine.” Regenerative medicine was a term coined to refer to medicine’s new-found ability to manufacture any cell type in the human body, based on embryonic stem (ES) cells. Normally, the confluence of such powerful economic forces would generate enormous new industries to connect the tides of supply and demand. And yet, in the United States today, the industry of regenerative medicine is still in its infancy, and we are hearing about the difficulties some companies face in commercializing the new products. This leads us to ask, “Where are the bottlenecks, and how will industry rise to the occasion to deliver on these desperately-needed new products?”
The problems facing our nation in regard to an aging population and the rising national health care bill have received high visibility in the media. Less well known, perhaps, is the daily struggle behind the scenes, as scientists seek to bring the promise of regenerative medicine to the marketplace. As we have said, ES cells, and their related cells called induced pluripotent stem (iPS) cells, have the impressive ability to become all the cell types in the human body. What is not as well appreciated is that this protean power resident in the cells is also an enormous hurdle for people working in biotechnology who wish to actually produce these products on an industrial scale. The challenge is one of purity. How do we consistently manufacture only the cell type of interest when there are hundreds of cell types in the body? If we do not solve these technical challenges, preclinical development costs can rise into the hundreds of millions of dollars, squelching product development.
These difficulties in the first decade of regenerative medicine will likely be addressed in the second decade by new methods to completely isolate and scale up defined lineages from ES or iPS cells. BioTime is using a proprietary approach we call ACTCellerateTM which has already resulted in the isolation of >200 different cell types of the human body. The use of these purified cell types is expected to simplify the manufacturing process and ease the concern of regulators over product safety. BioTime’s announcement of a partnership with GeneCards is the beginning of our effort to steer regenerative medicine into a new era wherein many new human cell types can be manufactured to scale at an unprecedented level of purity and identity. This new generation of manufacturing technologies, or as we say Manufacturing 2.0, is expected to simplify product development and speed the transfer of supply to demand.
But for the research scientist, accessing for the first time the purified cellular building blocks of the human body, and being able to map out their gene expression profiles, is as much an appreciation of the beauty of human development as it is a quest for cures and products. Seeing for the first time in the laboratory dish the cellular components of the human body, and being able to map out the genes that cause the cells to weave themselves into human tissues, gives the bench scientist a vision of what life could be, how medicine could fashion new life-saving therapies. Our nation cannot afford to lag behind in the commercialization of regenerative medicine in such a critical time in our nation’s history. Never before have we faced such opportunity in medical research, and never before has it mattered so much for so many people.
Tuesday, November 15, 2011
Sunday, May 15, 2011
An Update on iPS Cell Technology
by Michael D. West, Ph.D.
May 16, 2011
"Look here," said the Medical Man, "are you perfectly serious? Or is this a trick – like that ghost you showed us last Christmas?"
H.G Wells
The Time Machine
Most people in touch with current events, in particular, developments relating to science and medicine, have observed the growth of the industry called regenerative medicine. The field was born with the first isolation of human embryonic stem cells in 1998. These cells when propagated under laboratory conditions have the potential for the first time in history of being transformed into all the cell types of the human body. Therefore, the vision of this emerging industry is to invent a new field of medicine wherein the hundreds of cell types of the human body are manufactured to repair or regenerate tissues worn out from aging, trauma, or disease. Some salient examples would be cells that have the potential to regenerate heart muscle after a heart attack (something the heart cannot do on its own), or cells capable of rebuilding the brain destroyed in a stroke, or skin cells lost in a body burn, pancreatic cells missing in diabetes, retinal cells for macular degeneration, and so on.
Some of these cell types can already be manufactured on an industrial scale and could likely be used in all people without transplant rejection. These commercial opportunities are therefore the low-hanging fruit, coveted by biotechnology and large pharmaceutical companies. Examples of these off-the-shelf products could include: cartilage for osteoarthritis, retinal cells for macular degeneration, and cells designed to target cancers to deliver a toxic payload that destroys tumors. All of these are, logically, the front-runners in BioTime’s product development pipeline.
But what about all the other cell types in the body where transplant rejection is an issue? Here is where cloning technology enters the scene. In the late 1990s, some of us in the stem cell field attempted to understand how cloning worked in order to find a way of using an egg cell as a “cellular time machine,” to transform a patient’s cell back into an embryonic stem cell again. So, our goal was to clone stem cells, not people, and in the process find a means of making all cell types available to patients that would be identical and not rejected. We showed that cloning technology could do this in animal models, and amazingly, we even showed that it could reset the telomere clock of cellular aging (Science 288:665, 2000).
Over the following years, we and others began to characterize the molecules within the egg cell that were critical in making all of this actually work. A mere handful of molecules appeared to be the key players. These molecules could be delivered into any cell in your body, such as a skin cell, and they were shown to be able to reprogram the skin cell back in time to an embryonic cell. Because cloning was not actually used (and no embryos were made in the process) they were given the new name “induced pluripotent stem (iPS) cells” to distinguish them from embryonic stem cells, although they are very, very similar. There has been an enormous surge of interest in these cells because they were seen as a noncontroversial means of making the all-powerful stem cells, and because they could potentially allow medical science to make any cell type identical to a patient, thereby eliminating the fear of transplant rejection. BioTime scientists invented some of the key early patents while at Advanced Cell Technology. That intellectual property was later licensed to BioTime and is being used by our subsidiary ReCyte Therapeutics for the development of patient-specific vascular cells for the treatment of age-related heart disease.
Recently, however, dark clouds have begun to gather over the landscape of iPS cells produced using the viral technologies of the Japanese researcher Dr. Yamanaka and the U.S. researcher Dr. James Thomson. First there was the report from scientists at Advanced Cell Technology that cells made from iPS cells appeared to age prematurely. We at BioTime showed that indeed, the widely-studied iPS cell lines did indeed have prematurely aged telomeres (the clock of cellular aging) but we showed that it was possible by sorting through the cells to find cells with sufficient telomerase activity to rewind the clock (Regen. Med. 5(3):345-363). Dr. Homayoun Vaziri (the first author on that paper) and I have published a review on the topic available at http://www.futuremedicine.com/toc/rme/5/4 or from PubMed under the title, “Back to immortality: the restoration of embryonic telomere length during induced pluripotency.”
Then there were reports that iPS cells produced using the viral technologies of Drs. Yamanaka and Thomson had a large number of genetic mutations compared to normal cells such as human embryonic stem cells. More recently, the laboratory of Dr. Yang Xu at the University of California, San Diego reported in the journal Nature that cells made using Yamanaka’s iPS cell protocol were rejected in mice.
We can safely conclude that this rejection of the cells reported by Dr. Xu’s group is not a problem with embryonic stem cells since the researchers saw no such rejection when embryonic stem cells were used. In addition, it is unlikely that the problem is with the reprogramming process per se since we and others had previously shown that cells reprogrammed by nuclear transfer (cloning technology) showed no evidence of rejection (Nat Biotechnol. 20:689-696). So, in summary, as of today the commonly-used protocols of Drs. Yamanaka and Thomson to generate iPS cells appear to: 1) poorly reset telomere length, 2) cause an abnormally high level of genetic mutations, and 3) at least in the case of Yamanaka’s procedure, to produce cells that are rejected in animal models. Therefore, improvements in iPS cell technologies that solve these difficulties will have a significant competitive advantage.
The most logical path for companies aiming to lay a firm technological foundation for product development in regenerative medicine is to manufacture the majority of their initial products using master cell banks of well-characterized GMP grade human embryonic stem cells, aiming at products that can be used in all patients such as those targeting arthritis, retinal disorders, and cancer (off-the-shelf applications). Then, for products to be derived from reprogramming, we believe that the best path is for researchers to more closely mirror the pathways used in cloning such as with the ReCyte™ technology that do not use retroviruses.
ReCyte is different in numerous respects from the iPS cell techniques used by most laboratories. ReCyte uses the molecules commonly used in the derivation of iPS cells but they are delivered via the cellular extracts designed to rapidly reprogram not only the DNA but also other components within the nucleus of the cell. Like iPS technology, the resulting technique does not require embryo formation, but unlike traditional iPS cells, the technique has the advantage of more closely matching nuclear transfer.
The medical man in H.G. Well’s story The Time Machine was rightly skeptical concerning the existence of a machine to transport a human being forward or backward in time. But a cellular “time machine,” that is, the technologies to reprogram human cells back to an embryonic state, is a demonstrable reality today. The competitive advantages of our ReCyte reprogramming technology over traditional iPS cell methods are only just now beginning to be appreciated by the life science community. We therefore plan to aggressively develop the ReCyte platform in 2011, demonstrating the uniqueness of our method, and collaborating with the regenerative medicine community to accelerate its commercialization.
Please see my blog of July 26, 2010 titled “ES and iPS Cells: Which Holds the Future of Biotechnology?” for more background on the history of ES and iPS cells.
May 16, 2011
"Look here," said the Medical Man, "are you perfectly serious? Or is this a trick – like that ghost you showed us last Christmas?"
H.G Wells
The Time Machine
Most people in touch with current events, in particular, developments relating to science and medicine, have observed the growth of the industry called regenerative medicine. The field was born with the first isolation of human embryonic stem cells in 1998. These cells when propagated under laboratory conditions have the potential for the first time in history of being transformed into all the cell types of the human body. Therefore, the vision of this emerging industry is to invent a new field of medicine wherein the hundreds of cell types of the human body are manufactured to repair or regenerate tissues worn out from aging, trauma, or disease. Some salient examples would be cells that have the potential to regenerate heart muscle after a heart attack (something the heart cannot do on its own), or cells capable of rebuilding the brain destroyed in a stroke, or skin cells lost in a body burn, pancreatic cells missing in diabetes, retinal cells for macular degeneration, and so on.
Some of these cell types can already be manufactured on an industrial scale and could likely be used in all people without transplant rejection. These commercial opportunities are therefore the low-hanging fruit, coveted by biotechnology and large pharmaceutical companies. Examples of these off-the-shelf products could include: cartilage for osteoarthritis, retinal cells for macular degeneration, and cells designed to target cancers to deliver a toxic payload that destroys tumors. All of these are, logically, the front-runners in BioTime’s product development pipeline.
But what about all the other cell types in the body where transplant rejection is an issue? Here is where cloning technology enters the scene. In the late 1990s, some of us in the stem cell field attempted to understand how cloning worked in order to find a way of using an egg cell as a “cellular time machine,” to transform a patient’s cell back into an embryonic stem cell again. So, our goal was to clone stem cells, not people, and in the process find a means of making all cell types available to patients that would be identical and not rejected. We showed that cloning technology could do this in animal models, and amazingly, we even showed that it could reset the telomere clock of cellular aging (Science 288:665, 2000).
Over the following years, we and others began to characterize the molecules within the egg cell that were critical in making all of this actually work. A mere handful of molecules appeared to be the key players. These molecules could be delivered into any cell in your body, such as a skin cell, and they were shown to be able to reprogram the skin cell back in time to an embryonic cell. Because cloning was not actually used (and no embryos were made in the process) they were given the new name “induced pluripotent stem (iPS) cells” to distinguish them from embryonic stem cells, although they are very, very similar. There has been an enormous surge of interest in these cells because they were seen as a noncontroversial means of making the all-powerful stem cells, and because they could potentially allow medical science to make any cell type identical to a patient, thereby eliminating the fear of transplant rejection. BioTime scientists invented some of the key early patents while at Advanced Cell Technology. That intellectual property was later licensed to BioTime and is being used by our subsidiary ReCyte Therapeutics for the development of patient-specific vascular cells for the treatment of age-related heart disease.
Recently, however, dark clouds have begun to gather over the landscape of iPS cells produced using the viral technologies of the Japanese researcher Dr. Yamanaka and the U.S. researcher Dr. James Thomson. First there was the report from scientists at Advanced Cell Technology that cells made from iPS cells appeared to age prematurely. We at BioTime showed that indeed, the widely-studied iPS cell lines did indeed have prematurely aged telomeres (the clock of cellular aging) but we showed that it was possible by sorting through the cells to find cells with sufficient telomerase activity to rewind the clock (Regen. Med. 5(3):345-363). Dr. Homayoun Vaziri (the first author on that paper) and I have published a review on the topic available at http://www.futuremedicine.com/toc/rme/5/4 or from PubMed under the title, “Back to immortality: the restoration of embryonic telomere length during induced pluripotency.”
Then there were reports that iPS cells produced using the viral technologies of Drs. Yamanaka and Thomson had a large number of genetic mutations compared to normal cells such as human embryonic stem cells. More recently, the laboratory of Dr. Yang Xu at the University of California, San Diego reported in the journal Nature that cells made using Yamanaka’s iPS cell protocol were rejected in mice.
We can safely conclude that this rejection of the cells reported by Dr. Xu’s group is not a problem with embryonic stem cells since the researchers saw no such rejection when embryonic stem cells were used. In addition, it is unlikely that the problem is with the reprogramming process per se since we and others had previously shown that cells reprogrammed by nuclear transfer (cloning technology) showed no evidence of rejection (Nat Biotechnol. 20:689-696). So, in summary, as of today the commonly-used protocols of Drs. Yamanaka and Thomson to generate iPS cells appear to: 1) poorly reset telomere length, 2) cause an abnormally high level of genetic mutations, and 3) at least in the case of Yamanaka’s procedure, to produce cells that are rejected in animal models. Therefore, improvements in iPS cell technologies that solve these difficulties will have a significant competitive advantage.
The most logical path for companies aiming to lay a firm technological foundation for product development in regenerative medicine is to manufacture the majority of their initial products using master cell banks of well-characterized GMP grade human embryonic stem cells, aiming at products that can be used in all patients such as those targeting arthritis, retinal disorders, and cancer (off-the-shelf applications). Then, for products to be derived from reprogramming, we believe that the best path is for researchers to more closely mirror the pathways used in cloning such as with the ReCyte™ technology that do not use retroviruses.
ReCyte is different in numerous respects from the iPS cell techniques used by most laboratories. ReCyte uses the molecules commonly used in the derivation of iPS cells but they are delivered via the cellular extracts designed to rapidly reprogram not only the DNA but also other components within the nucleus of the cell. Like iPS technology, the resulting technique does not require embryo formation, but unlike traditional iPS cells, the technique has the advantage of more closely matching nuclear transfer.
The medical man in H.G. Well’s story The Time Machine was rightly skeptical concerning the existence of a machine to transport a human being forward or backward in time. But a cellular “time machine,” that is, the technologies to reprogram human cells back to an embryonic state, is a demonstrable reality today. The competitive advantages of our ReCyte reprogramming technology over traditional iPS cell methods are only just now beginning to be appreciated by the life science community. We therefore plan to aggressively develop the ReCyte platform in 2011, demonstrating the uniqueness of our method, and collaborating with the regenerative medicine community to accelerate its commercialization.
Please see my blog of July 26, 2010 titled “ES and iPS Cells: Which Holds the Future of Biotechnology?” for more background on the history of ES and iPS cells.
Friday, January 28, 2011
Mr. Monk, Stem Cells, and Cancer
by Michael D. West, Ph.D.
January 28, 2011
“It’s a jungle out there
Disorder and confusion everywhere…
You better pay attention
or the world we love so much
might just kill you.” (Monk theme song)
The lead character in the television program “Monk” is a detective named Adrian with obsessive-compulsive disorder who vainly attempts to organize the world around him, lining up bullet casings in a row as he explains the details of the murder plot.
The cells in our bodies, like Mr. Monk, hate disorder and confusion. And there is a very good reason for this. Packed away inside the trillions of cells in our body is a set of each and every human gene, highly organized in a row along the string of DNA. This genetic blueprint contains all the information to make us who we are. These genes even direct human development (the amazing process that allows us to live even while we are being formed from a single cell). If this precise organization of DNA becomes disordered, powerful and deadly changes can be unleashed. Some deleterious changes have an effect similar to a stuck accelerator in a car, causing the cells to divide rapidly. Other genes, if broken, function like a defective brake, eliminating the normal mechanisms that regulate tissue size. Lastly, the inappropriate expression of the immortalizing gene called telomerase can give cells an infinite fuel supply, i.e. an unnatural ability to replicate without limit. These disorderly events, if they occur together in one cell, can lead to the disastrous outcome similar to a car with a stuck accelerator, a broken brake, and an infinite fuel supply all at the same time. This would be a very dangerous result indeed - somebody is going to die as a result. And they do die, because this cellular calamity is known as cancer.
Cancer is the second leading cause of death in the United States, a toll of over half a million fatalities in the US every year. We frequently hear that one of the reasons cancer researchers have made little progress in eliminating the disease is that there are many types of cancer, and there are many different genes that can be involved. As a result of the slow progress in finding new and effective therapies, many of the techniques currently used in front-line treatment are conceptually quite primitive. They are known as cut/poison/burn strategies. Tumors are surgically removed (cut), treated with chemotherapeutic agents (poisoned), or targeted with radiation (burned). These techniques are marginally effective, however, since cancer cells have gained the ability to proliferate indefinitely, only a few remaining cells can seed the growth of new tumors that can spread wildly out of control throughout the body until they kill you. And so, many cancer therapeutics used today are not cures, they just delay the inevitable.
Surgery has been used to treat cancer for centuries, while chemotherapy and radiation have been used for over fifty years. But physicians, biomedical researchers, and pharmaceutical companies have developed some newer strategies for treating cancer over the last couple of decades as well. One pioneering researcher, the late Dr. Judah Folkman, through some very clever detective work of his own, demonstrated that there is a potential Achilles heel common to many tumors such as breast, colon, lung, and prostate cancers. Malignant tumors need blood vessels to bring in the nutrition to feed their rapid growth. This has led to many current clinical trials of drugs and antibodies designed to block the growth of new blood vessels associated with cancer. Unfortunately, like so many strategies tried before, many of these trials have been disappointing, in part because cells have multiple ways of attracting blood supply. Blocking only one of them leads to the selection of alternative means of feeding the tumor, and the cancer, after finding a detour around the blockade, continues its relentless course.
In BioTime’s subsidiary OncoCyte, we are building upon these previous insights into cancer to develop an entirely new class of cancer therapeutics. Our technology builds on the insight that blood supply is a sine qua non for tumor growth. But rather than trying to stop the growth of the blood vessels feeding the tumors, we are in effect saying, “Fine, go ahead and be cells proliferating out of control. But if you do, you will die.” Here is our strategy in brief. We plan to introduce into the blood of patients with cancer certain types of cells designed to target and destroy tumors. These cells were recently made available from human embryonic stem (hES) and induced pluripotent (iPS) cells. We believe that they can be made to target the vascular system supporting the tumor. In a manner similar to the story of the Trojan horse, getting the cells into the vasculature of the tumor is like surreptitiously getting them into the front gate of the enemy. Next we utilize another useful property of hES and iPS cells: they can be precisely genetically engineered. These genetic modifications are intended to allow a physician to send a signal (such as by a beam of X-rays), to turn on genes to destroy the tumor from within.
Today’s announced acquisition of the assets of Cell Targeting, Inc., a company specializing in “painting” cells with peptides to target them to sites of disease such as cancer, damaged heart tissue, or wounds in the skin, is part of BioTime’s strategic plan to assemble an array of ancillary technologies useful in translating our novel cells into effective therapeutics. Despite the fact that cancer historically has been a notoriously difficult target to hit, we believe that new medical technologies provide potent new weapons that may turn the tide on the battle. The enormous advances in our understanding of DNA, coupled with the birth of the field of regenerative medicine, have created an opportunity to attack cancer in entirely new ways. OncoCyte is pursuing the development of science, technology, and intellectual property that will form the foundation of these new strategies. Over time we hope to also develop successful new therapies that may be able to reduce the vast human toll that cancer continues to take every year. The development of therapies takes time, and no cure for cancer is available today. But each step forward is one day closer to striking at the heart of this devastating disease.
January 28, 2011
“It’s a jungle out there
Disorder and confusion everywhere…
You better pay attention
or the world we love so much
might just kill you.” (Monk theme song)
The lead character in the television program “Monk” is a detective named Adrian with obsessive-compulsive disorder who vainly attempts to organize the world around him, lining up bullet casings in a row as he explains the details of the murder plot.
The cells in our bodies, like Mr. Monk, hate disorder and confusion. And there is a very good reason for this. Packed away inside the trillions of cells in our body is a set of each and every human gene, highly organized in a row along the string of DNA. This genetic blueprint contains all the information to make us who we are. These genes even direct human development (the amazing process that allows us to live even while we are being formed from a single cell). If this precise organization of DNA becomes disordered, powerful and deadly changes can be unleashed. Some deleterious changes have an effect similar to a stuck accelerator in a car, causing the cells to divide rapidly. Other genes, if broken, function like a defective brake, eliminating the normal mechanisms that regulate tissue size. Lastly, the inappropriate expression of the immortalizing gene called telomerase can give cells an infinite fuel supply, i.e. an unnatural ability to replicate without limit. These disorderly events, if they occur together in one cell, can lead to the disastrous outcome similar to a car with a stuck accelerator, a broken brake, and an infinite fuel supply all at the same time. This would be a very dangerous result indeed - somebody is going to die as a result. And they do die, because this cellular calamity is known as cancer.
Cancer is the second leading cause of death in the United States, a toll of over half a million fatalities in the US every year. We frequently hear that one of the reasons cancer researchers have made little progress in eliminating the disease is that there are many types of cancer, and there are many different genes that can be involved. As a result of the slow progress in finding new and effective therapies, many of the techniques currently used in front-line treatment are conceptually quite primitive. They are known as cut/poison/burn strategies. Tumors are surgically removed (cut), treated with chemotherapeutic agents (poisoned), or targeted with radiation (burned). These techniques are marginally effective, however, since cancer cells have gained the ability to proliferate indefinitely, only a few remaining cells can seed the growth of new tumors that can spread wildly out of control throughout the body until they kill you. And so, many cancer therapeutics used today are not cures, they just delay the inevitable.
Surgery has been used to treat cancer for centuries, while chemotherapy and radiation have been used for over fifty years. But physicians, biomedical researchers, and pharmaceutical companies have developed some newer strategies for treating cancer over the last couple of decades as well. One pioneering researcher, the late Dr. Judah Folkman, through some very clever detective work of his own, demonstrated that there is a potential Achilles heel common to many tumors such as breast, colon, lung, and prostate cancers. Malignant tumors need blood vessels to bring in the nutrition to feed their rapid growth. This has led to many current clinical trials of drugs and antibodies designed to block the growth of new blood vessels associated with cancer. Unfortunately, like so many strategies tried before, many of these trials have been disappointing, in part because cells have multiple ways of attracting blood supply. Blocking only one of them leads to the selection of alternative means of feeding the tumor, and the cancer, after finding a detour around the blockade, continues its relentless course.
In BioTime’s subsidiary OncoCyte, we are building upon these previous insights into cancer to develop an entirely new class of cancer therapeutics. Our technology builds on the insight that blood supply is a sine qua non for tumor growth. But rather than trying to stop the growth of the blood vessels feeding the tumors, we are in effect saying, “Fine, go ahead and be cells proliferating out of control. But if you do, you will die.” Here is our strategy in brief. We plan to introduce into the blood of patients with cancer certain types of cells designed to target and destroy tumors. These cells were recently made available from human embryonic stem (hES) and induced pluripotent (iPS) cells. We believe that they can be made to target the vascular system supporting the tumor. In a manner similar to the story of the Trojan horse, getting the cells into the vasculature of the tumor is like surreptitiously getting them into the front gate of the enemy. Next we utilize another useful property of hES and iPS cells: they can be precisely genetically engineered. These genetic modifications are intended to allow a physician to send a signal (such as by a beam of X-rays), to turn on genes to destroy the tumor from within.
Today’s announced acquisition of the assets of Cell Targeting, Inc., a company specializing in “painting” cells with peptides to target them to sites of disease such as cancer, damaged heart tissue, or wounds in the skin, is part of BioTime’s strategic plan to assemble an array of ancillary technologies useful in translating our novel cells into effective therapeutics. Despite the fact that cancer historically has been a notoriously difficult target to hit, we believe that new medical technologies provide potent new weapons that may turn the tide on the battle. The enormous advances in our understanding of DNA, coupled with the birth of the field of regenerative medicine, have created an opportunity to attack cancer in entirely new ways. OncoCyte is pursuing the development of science, technology, and intellectual property that will form the foundation of these new strategies. Over time we hope to also develop successful new therapies that may be able to reduce the vast human toll that cancer continues to take every year. The development of therapies takes time, and no cure for cancer is available today. But each step forward is one day closer to striking at the heart of this devastating disease.
Sunday, November 28, 2010
Banking on the Future of Regenerative Medicine
by Michael D. West, Ph.D.
November 29, 2010
Human embryonic stem (hES) cells are widely known for their capacity to branch into all of the cell types in the human body. This unprecedented potentiality has spurred a new industry called “regenerative medicine” in anticipation of a time when medicine can offer many therapies not possible today. Many have also heard that these cells also have the unusual property of being able to proliferate without limit (without aging), though perhaps most people have not quite known what that really means or its implications for this emerging industry. It is my view that these twin properties of hES cells (i.e. their pluripotentiality and their ability to replicate without limit) will make it possible to standardize foundational master cell banks of these cells that could be a continuous source of a wide array of human clinical grade products around the globe and for many years to come. For industry, the remaining question is: “What is the best strategic business model for a company to take given the unprecedented potential of these cells?”
The story on stem cell banking begins in the years following the first isolation of hES cells (1998). Almost immediately, governments from around the world recognized that the technology could be used to improve health care and reduce health care costs associated with expensive chronic degenerative diseases such as those associated with an aging population. The Government of Singapore became one such leader in the field of embryonic stem cell research. The Economic Development Board of Singapore had the vision to fund a commercial effort centered in ES Cell International (ESI), a company that eventually became the first to generate a bank of six clinical grade human embryonic stem cell lines. These cell lines were the first such lines produced under conditions consistent with Good Manufacturing Practices (GMP) in that the donors were carefully screened for medical history, and every step and component used in the production of the lines was carefully documented in an effort to comply with guidelines provided by the U.S. FDA Center for Biologics Evaluation and Research regarding human cell-based products (HCT/Ps).
Another step forward occurred in November 2004 when the people of California adopted Proposition 71 (the California Stem Cell Research and Cures Act) to fund $3 billion worth of stem cell research and development in California. The resulting California Institute for Regenerative Medicine (CIRM) was given the mission to determine where funds should be distributed in order to accelerate stem cell based research into the development of vital cures and the treatment of debilitating injuries.
On April 29, 2010 BioTime announced the acquisition of ESI. Our primary interest in this transaction was to make ESI’s GMP-compliant hES cell bank foundational not only for BioTime’s product development, but also for as much of the rest of the world as possible. Therefore, today BioTime and CIRM announced a collaborative agreement whereby five of the six clinical grade lines will be shared with California-based researchers (one of the lines is being reserved for a potential commercial relationship). In the agreement, BioTime agrees to initially provide research grade versions of the lines for research use only (not commercial use) to California-based researchers. These will be offered for free within California until April 30, 2011. This could streamline the process for California-based scientists by allowing them to use the same cell line in their research that will later potentially be used in the clinic. Within a year of the signing of the agreement, BioTime agrees to make the actual GMP grade lines available to the CIRM grantees and California researchers requesting the lines at a price approximating BioTime’s cost of producing and supplying the cell lines.
In the coming years of grant funding as potential products emerge for various applications in medicine, BioTime agrees to negotiate in good faith with the relevant parties to provide the GMP cell lines for use in manufacturing commercial products with a royalty on net sales not to exceed 2% (or 1.5% if other royalties are owed). The pre-negotiation of terms will serve to help accelerate research by eliminating protracted negotiations. The nature of therapeutic products emerging from the $3 billion CIRM program and the potential revenues from such products remains to be determined. However, several reports are available online that make projections of potential return on investment for California citizens.
And so, in an attempt to answer the question I posed at the start about the optimum business strategy, we have chosen a plan of making our ESI cGMP-compliant cell lines widely available to researchers. By taking this path, BioTime intends to both facilitate the development of life-saving therapies around the world, and to standardize the ESI lines as one of the best-characterized master cell banks from which to manufacture human cell-based therapies. If we can succeed in these aims, we have the potential in future years to simultaneously benefit BioTime shareholders and patients in need of these new therapies.
November 29, 2010
Human embryonic stem (hES) cells are widely known for their capacity to branch into all of the cell types in the human body. This unprecedented potentiality has spurred a new industry called “regenerative medicine” in anticipation of a time when medicine can offer many therapies not possible today. Many have also heard that these cells also have the unusual property of being able to proliferate without limit (without aging), though perhaps most people have not quite known what that really means or its implications for this emerging industry. It is my view that these twin properties of hES cells (i.e. their pluripotentiality and their ability to replicate without limit) will make it possible to standardize foundational master cell banks of these cells that could be a continuous source of a wide array of human clinical grade products around the globe and for many years to come. For industry, the remaining question is: “What is the best strategic business model for a company to take given the unprecedented potential of these cells?”
The story on stem cell banking begins in the years following the first isolation of hES cells (1998). Almost immediately, governments from around the world recognized that the technology could be used to improve health care and reduce health care costs associated with expensive chronic degenerative diseases such as those associated with an aging population. The Government of Singapore became one such leader in the field of embryonic stem cell research. The Economic Development Board of Singapore had the vision to fund a commercial effort centered in ES Cell International (ESI), a company that eventually became the first to generate a bank of six clinical grade human embryonic stem cell lines. These cell lines were the first such lines produced under conditions consistent with Good Manufacturing Practices (GMP) in that the donors were carefully screened for medical history, and every step and component used in the production of the lines was carefully documented in an effort to comply with guidelines provided by the U.S. FDA Center for Biologics Evaluation and Research regarding human cell-based products (HCT/Ps).
Another step forward occurred in November 2004 when the people of California adopted Proposition 71 (the California Stem Cell Research and Cures Act) to fund $3 billion worth of stem cell research and development in California. The resulting California Institute for Regenerative Medicine (CIRM) was given the mission to determine where funds should be distributed in order to accelerate stem cell based research into the development of vital cures and the treatment of debilitating injuries.
On April 29, 2010 BioTime announced the acquisition of ESI. Our primary interest in this transaction was to make ESI’s GMP-compliant hES cell bank foundational not only for BioTime’s product development, but also for as much of the rest of the world as possible. Therefore, today BioTime and CIRM announced a collaborative agreement whereby five of the six clinical grade lines will be shared with California-based researchers (one of the lines is being reserved for a potential commercial relationship). In the agreement, BioTime agrees to initially provide research grade versions of the lines for research use only (not commercial use) to California-based researchers. These will be offered for free within California until April 30, 2011. This could streamline the process for California-based scientists by allowing them to use the same cell line in their research that will later potentially be used in the clinic. Within a year of the signing of the agreement, BioTime agrees to make the actual GMP grade lines available to the CIRM grantees and California researchers requesting the lines at a price approximating BioTime’s cost of producing and supplying the cell lines.
In the coming years of grant funding as potential products emerge for various applications in medicine, BioTime agrees to negotiate in good faith with the relevant parties to provide the GMP cell lines for use in manufacturing commercial products with a royalty on net sales not to exceed 2% (or 1.5% if other royalties are owed). The pre-negotiation of terms will serve to help accelerate research by eliminating protracted negotiations. The nature of therapeutic products emerging from the $3 billion CIRM program and the potential revenues from such products remains to be determined. However, several reports are available online that make projections of potential return on investment for California citizens.
And so, in an attempt to answer the question I posed at the start about the optimum business strategy, we have chosen a plan of making our ESI cGMP-compliant cell lines widely available to researchers. By taking this path, BioTime intends to both facilitate the development of life-saving therapies around the world, and to standardize the ESI lines as one of the best-characterized master cell banks from which to manufacture human cell-based therapies. If we can succeed in these aims, we have the potential in future years to simultaneously benefit BioTime shareholders and patients in need of these new therapies.
Sunday, October 10, 2010
The Cyclic Nature of Biotech Revolutions
by Michael D. West, Ph.D.
October 10, 2010
We all can probably remember a time when we met someone who indelibly impacted our lives. In the mid 1990s my life was influenced by a series of meetings I had with Bob Swanson, one of the founders of Genentech. Bob was a man with extraordinary vision, a near clairvoyant ability to sense business trends. Upon being briefed on the then-confidential project to isolate human embryonic stem cells, he pulled me aside and whispered something like the following:
“So here is how it will all play out. First off, this will be a really big deal. It will be like recombinant DNA, a revolution that will change everything. And like recombinant DNA, it will be very controversial. I used to spend most of my time in Senate hearings explaining that we were not trying to play god, or create an Andromeda Strain or something like that. Then with time the technology will become part of the establishment of science, the clouds of controversy will blow over, and that is when the real business will begin. That is when big pharma will enter the field."
During most of the history of biotechnology, small companies have been the hotbed of medical innovation. But these small firms generally lack the capital to fund the expensive clinical trials necessary for FDA approval and launch of new therapeutics. Therefore, the biotechnology industry has long depended on partnerships with large, profitable pharmaceutical companies to help them fund this work. In reward for funding the development costs, the large partner gets to sell the final product and capture the lion’s share of profits. And the smaller biotechnology company is generally rewarded with up-front monies, substantial milestone payments, and a royalty on future product sales.
The problem with this model is that many biotech companies do not have a broad technology platform; they sometimes have only one or two products, and therefore these collaborations often “give away the shop,” leaving little left for the company to develop on its own. In the case of companies in the emerging field of regenerative medicine using human embryonic stem (hES) cells, the problem is not one of giving away the shop. There are many hundreds of potential new therapeutics possible now that we have a means of manufacturing all the cell types of the human body.
The problem in the case of hES cells, as predicted by Bob Swanson back in the mid 1990s, has been in part the clouds of ethical controversy. The ethical debate has slowed the entry of large pharmaceutical companies into the field. But as Bob also predicted with hES cells, and as we saw play out in the previous controversies over recombinant DNA, these important new revolutions in medicines are progressively entering mainstream therapeutic development. The skies really began to clear with the State of California funding $3 billion to advance the technology and with President Obama’s efforts to free up federally funded research. And with those clear skies, deals are beginning to take place.
On October 10, 2010, BioTime announced a deal between BioTime’s majority-owned subsidiary Cell Cure Neurosciences Ltd. and the pharma giant Teva Pharmaceutical Industries Ltd., both based in Israel. This is the first in what we hope will become a series of strategic corporate alliances for BioTime subsidiaries that will fund the expensive development costs of a wide array of therapeutics in a manner minimizing equity financing and consequent dilution to BioTime shareholders.
In the Cell Cure/Teva agreement, Teva has an option to complete clinical development and to commercialize one cell type – retinal pigment epithelial (RPE) cells for the treatment of retinal disease. While the potential market for a treatment for macular degeneration is very large (some seven million Americans are at risk of the disease), this agreement still leaves all of our other potential therapeutic products, including the greater than 140 diverse and scalable progenitor cell types that we have isolated from hES cells, open for future possibilities, including commercialization.
Our subsidiary strategy also allows the management of each subsidiary to focus on a specific therapeutic area. In the case of Cell Cure, there is a dual focus on neurological and retinal disease. So building subsidiaries in particular disease applications facilitates the optimization of the science and commercial collaborations to improve the probability of that company becoming an industry leader.
Cell Cure’s agreement with Teva is, to the best of our knowledge, the first collaboration in the embryonic stem cell space between a large pharma company and a subsidiary of a public stem cell company. We hope, for the sake of patients, and for the future of the stem cell industry, that many more such commercial agreements will follow, speeding the delivery of new cell-based therapies to the patients who so desperately need them.
October 10, 2010
We all can probably remember a time when we met someone who indelibly impacted our lives. In the mid 1990s my life was influenced by a series of meetings I had with Bob Swanson, one of the founders of Genentech. Bob was a man with extraordinary vision, a near clairvoyant ability to sense business trends. Upon being briefed on the then-confidential project to isolate human embryonic stem cells, he pulled me aside and whispered something like the following:
“So here is how it will all play out. First off, this will be a really big deal. It will be like recombinant DNA, a revolution that will change everything. And like recombinant DNA, it will be very controversial. I used to spend most of my time in Senate hearings explaining that we were not trying to play god, or create an Andromeda Strain or something like that. Then with time the technology will become part of the establishment of science, the clouds of controversy will blow over, and that is when the real business will begin. That is when big pharma will enter the field."
During most of the history of biotechnology, small companies have been the hotbed of medical innovation. But these small firms generally lack the capital to fund the expensive clinical trials necessary for FDA approval and launch of new therapeutics. Therefore, the biotechnology industry has long depended on partnerships with large, profitable pharmaceutical companies to help them fund this work. In reward for funding the development costs, the large partner gets to sell the final product and capture the lion’s share of profits. And the smaller biotechnology company is generally rewarded with up-front monies, substantial milestone payments, and a royalty on future product sales.
The problem with this model is that many biotech companies do not have a broad technology platform; they sometimes have only one or two products, and therefore these collaborations often “give away the shop,” leaving little left for the company to develop on its own. In the case of companies in the emerging field of regenerative medicine using human embryonic stem (hES) cells, the problem is not one of giving away the shop. There are many hundreds of potential new therapeutics possible now that we have a means of manufacturing all the cell types of the human body.
The problem in the case of hES cells, as predicted by Bob Swanson back in the mid 1990s, has been in part the clouds of ethical controversy. The ethical debate has slowed the entry of large pharmaceutical companies into the field. But as Bob also predicted with hES cells, and as we saw play out in the previous controversies over recombinant DNA, these important new revolutions in medicines are progressively entering mainstream therapeutic development. The skies really began to clear with the State of California funding $3 billion to advance the technology and with President Obama’s efforts to free up federally funded research. And with those clear skies, deals are beginning to take place.
On October 10, 2010, BioTime announced a deal between BioTime’s majority-owned subsidiary Cell Cure Neurosciences Ltd. and the pharma giant Teva Pharmaceutical Industries Ltd., both based in Israel. This is the first in what we hope will become a series of strategic corporate alliances for BioTime subsidiaries that will fund the expensive development costs of a wide array of therapeutics in a manner minimizing equity financing and consequent dilution to BioTime shareholders.
In the Cell Cure/Teva agreement, Teva has an option to complete clinical development and to commercialize one cell type – retinal pigment epithelial (RPE) cells for the treatment of retinal disease. While the potential market for a treatment for macular degeneration is very large (some seven million Americans are at risk of the disease), this agreement still leaves all of our other potential therapeutic products, including the greater than 140 diverse and scalable progenitor cell types that we have isolated from hES cells, open for future possibilities, including commercialization.
Our subsidiary strategy also allows the management of each subsidiary to focus on a specific therapeutic area. In the case of Cell Cure, there is a dual focus on neurological and retinal disease. So building subsidiaries in particular disease applications facilitates the optimization of the science and commercial collaborations to improve the probability of that company becoming an industry leader.
Cell Cure’s agreement with Teva is, to the best of our knowledge, the first collaboration in the embryonic stem cell space between a large pharma company and a subsidiary of a public stem cell company. We hope, for the sake of patients, and for the future of the stem cell industry, that many more such commercial agreements will follow, speeding the delivery of new cell-based therapies to the patients who so desperately need them.
Tuesday, August 24, 2010
A 2020 Vision for Health Care Priorities in the United States
by Michael D. West, Ph.D.
August 24, 2010
On August 23, 2010, Judge Royce C. Lamberth of the United States District Court for the District of Columbia opined on the case of Drs. James L. Sherley and Theresa Deisher, Nightlight Christian Adoptions (“Nightlight”), Embryos, Shayne and Tina Nelson, William and Patricia Flynn, and Christian Medical Association (“CMA”) who brought a suit for declaratory and injunctive relief to prevent the National Institutes of Health from funding human embryonic stem (hES) cell research under their “Guidelines for Human Stem Cell Research.” One question that comes up in all this is what is the impact of these federal policy reversals on biotechnology companies.
I believe the issues at hand have less to do with corporate business plans that they do with public health policy. Here is where I take off the CEO of a biotech company hat and put on the hat of a human being with friends and loved ones in need of new medical therapies. Human ES cells have spawned the new field of regenerative medicine because of their potential to be used in making all of the cell types of the human body for the first time in the history of medicine. This is the basis of the reasonable anticipation that they could be used to repair the tissues of the human body afflicted with degenerative disease. The cells were originally isolated with private biotech funds. And it has always been the case that a prohibition of federally funded research gives private biotech companies a less competitive environment in which to operate. Since there are no federal restrictions on privately funded hES cell research, biotech can potentially make relatively more discoveries and file more patents if we have no competition from academic groups like Harvard, MIT, and Stanford. But the reason I have been an advocate of federal funding for so long, is not that we receive or depend upon federal grants (we have none). Rather, the reason is that hES cells have the potential to cure many chronic and devastating degenerative diseases about to cripple our health care system.
Age-related degenerative diseases such as osteoarthritis, heart failure, macular degeneration, and type II diabetes, to name just a few, are rapidly increasing in frequency with the aging of our baby boom population. Unless our country tackles these problems very soon, we will be left with years of medical expenses totaling trillions of dollars, projected by even conservative estimates to break the US economy and severely compromise our productivity. As disciplined as we may be as a small biotech company, BioTime cannot develop all of the dozens or even hundreds of medical therapies possible with hES cell technology all by ourselves. The smart thing for our country, indeed for the developed world, is to prepare for the age wave of degenerative disease by aggressively funding the emerging field of regenerative medicine, taking a rational and compassionate approach to the application of science and technology for the human good. BioTime’s management would welcome competition from academia for patents if the results were an acceleration of the pace of new therapies for these life-threatening diseases. If we are to maintain the US as a competitive economy, it is essential to have a vision and strategic plan of tackling the coming wave of degenerative diseases in the year 2020 through aggressive national funding of the field of regenerative medicine.
August 24, 2010
On August 23, 2010, Judge Royce C. Lamberth of the United States District Court for the District of Columbia opined on the case of Drs. James L. Sherley and Theresa Deisher, Nightlight Christian Adoptions (“Nightlight”), Embryos, Shayne and Tina Nelson, William and Patricia Flynn, and Christian Medical Association (“CMA”) who brought a suit for declaratory and injunctive relief to prevent the National Institutes of Health from funding human embryonic stem (hES) cell research under their “Guidelines for Human Stem Cell Research.” One question that comes up in all this is what is the impact of these federal policy reversals on biotechnology companies.
I believe the issues at hand have less to do with corporate business plans that they do with public health policy. Here is where I take off the CEO of a biotech company hat and put on the hat of a human being with friends and loved ones in need of new medical therapies. Human ES cells have spawned the new field of regenerative medicine because of their potential to be used in making all of the cell types of the human body for the first time in the history of medicine. This is the basis of the reasonable anticipation that they could be used to repair the tissues of the human body afflicted with degenerative disease. The cells were originally isolated with private biotech funds. And it has always been the case that a prohibition of federally funded research gives private biotech companies a less competitive environment in which to operate. Since there are no federal restrictions on privately funded hES cell research, biotech can potentially make relatively more discoveries and file more patents if we have no competition from academic groups like Harvard, MIT, and Stanford. But the reason I have been an advocate of federal funding for so long, is not that we receive or depend upon federal grants (we have none). Rather, the reason is that hES cells have the potential to cure many chronic and devastating degenerative diseases about to cripple our health care system.
Age-related degenerative diseases such as osteoarthritis, heart failure, macular degeneration, and type II diabetes, to name just a few, are rapidly increasing in frequency with the aging of our baby boom population. Unless our country tackles these problems very soon, we will be left with years of medical expenses totaling trillions of dollars, projected by even conservative estimates to break the US economy and severely compromise our productivity. As disciplined as we may be as a small biotech company, BioTime cannot develop all of the dozens or even hundreds of medical therapies possible with hES cell technology all by ourselves. The smart thing for our country, indeed for the developed world, is to prepare for the age wave of degenerative disease by aggressively funding the emerging field of regenerative medicine, taking a rational and compassionate approach to the application of science and technology for the human good. BioTime’s management would welcome competition from academia for patents if the results were an acceleration of the pace of new therapies for these life-threatening diseases. If we are to maintain the US as a competitive economy, it is essential to have a vision and strategic plan of tackling the coming wave of degenerative diseases in the year 2020 through aggressive national funding of the field of regenerative medicine.
Monday, July 26, 2010
ES and iPS Cells: Which Holds the Future of Biotechnology?
by Michael D. West, Ph.D.
July 26, 2010
New developments in stem cell technology offer significant promise for the future of medicine. Human embryonic stem (ES) cells and induced pluripotent stem (iPS) cells are the two sides of the coin of regenerative medicine. Many people ask, “Which of these are the most important, and which holds the future of lifesaving medical therapies?” I believe both will be critical in the coming years. To see why, let me share some of our thoughts in the early years of this technology. By tracing the flow of this history I think it will be possible to bring into focus the big picture.
Medicine has long wished for a means of repairing the hundreds of diverse tissues in the human body. Organ transplantation has become one way of doing this, but its use is severely limited by two things. First, the majority of people in need of tissue never find a compatible donor. The reason for this is that it is quite rare to find organs that are a close match to a given patient. Second, cells and tissues from adult tissues are limited in their ability to regenerate. If they could regenerate, we would simply re-grow amputated arms and legs after they were lost, heart tissue would regenerate after a heart attack, and brain cells would repair the damage occurring in Parkinson’s disease.
The History of ES Cells:
In the mid 1990’s when I was at Geron Corporation, we launched a project to isolate cells we thought could revolutionize this field. The concept was that, theoretically at least, there were cells in the first few days of human life that could form all the cells of the human body. The idea was that if we could capture these cells and cause them to proliferate in the laboratory dish as cell lines, that is to say, cultures where we could expand them into millions and millions of cells without them beginning to differentiate into the cells of the body, we could invent a scalable source of any cell type of the human body. Then we could take these all-powerful stem cells and turn on the molecular switches that would cause them to become anything we needed to make, that is, cartilage for the treatment of arthritis, blood cells for leukemia patients, or cells to produce insulin for diabetics, and so on. We found collaborators in Drs. Roger Petersen at UCSF, James Thomson at the University of Wisconsin at Madison, and John Gearhart at Johns Hopkins University School of Medicine and the race was on to create these cells. As a result of this collaboration, the first human embryonic stem cells were derived in 1998.
Therapeutic Cloning:
Then in 1997 came the advent of animal cloning. Cloning is a technique where the DNA removed from an egg cell is replaced with that of one of the cells of the body of an adult animal. When this is done, amazing things happen. Something in the egg cell changes the DNA of the cell from the body, perhaps a skin cell, and transforms that cell back to the embryonic state wherein the cell has totipotency (the ability to become all the cell types in the body). If this cluster of cells is transferred to a uterus, the cells may attach to begin a pregnancy and perhaps a live born animal, the genetic twin of the animal from which the original cells were obtained.
The first mammal to be cloned in this manner came from a breast epithelial cell, and was named “Dolly” after Dolly Parton. Shortly after Dolly was cloned, some of us proposed using cloning technology in the human species, but not to clone human beings, rather to clone ES cells. This was called “therapeutic cloning” as opposed to “reproductive cloning” (i.e. the cloning of a baby) (Nature Medicine 5(9): 975-977). The promising nature of this technology to us was that this technique could potentially allow medicine to do something that has always been outside its reach; namely to make any type of cell or tissue available in any quantity genetically identical to the patient, thereby obviating transplant rejection for human donors. In addition, we had reasons to believe that cloning technology just might act like a cellular “time machine” to reset the clock of cellular aging by restoring embryonic telomere length (the clock of cellular aging). We showed this was indeed the case, at least in the bovine species in 2000 (Science 288: 665-669).
So the vision was to take a cell from a patient, some cell easy to part with like one from a plucked hair follicle, or a blood cell, then to take that cell back in time using the molecules in the egg cell. Again, the goal was to produce young cells of any kind for old people. The goal never was to clone babies and human beings. We then showed preliminary success in cloning human cells at the earliest stages of life, the cloning of preimplantation embryos (e-biomed: J. Regen. Med. 2: 25-31). However, we were not successful in deriving stem cell lines from these reprogrammed cells (and to my knowledge, no one yet has).
There was, of course, a great deal of controversy over therapeutic cloning. While we said that these early clusters of cells are not yet an individual human being (some of my testimony on that subject can be found at http://michaelwest.org/testimony.htm), others disagreed and vociferously argued that therapeutic cloning, despite any potential benefit to people suffering from degenerative disease, ought to be illegal.
However, the greatest difficulty, in my opinion, was not this ethical controversy over the legal status of preimplantation embryos. Even some theologians have concluded that human life should be considered to begin at about 14 days after fertilization, way beyond the stages of life used in stem cell technology. An example of this would be Norman Ford’s thoughtful analysis in the book “When did I begin?” To me, the real difficulty with therapeutic cloning was the source of the active ingredient in the whole process: the human egg cell. We would need millions of egg cells a year to meet the need of those in need of regenerative therapy. Since young women need to be the source of these cells, a large percentage of these women would need to display a beneficence not yet observed in medical donation.
iPS Cells:
In the years 1999-2005 a number of patent applications were filed on what one might call a “cloning machine.” The idea was to define the molecules in an egg cell that made cloning work and then construct a robotic platform using these molecules to transport a patient’s cells back in time without making embryos or without using egg cells. We at BioTime now call this proprietary process “ReCyte™.” In 2007 the Japanese researcher Shinya Yamanaka and the University of Wisconsin-based researcher James Thomson published the first papers showing that four master regulatory genes could reprogram cells from the human body back to an embryonic state. Since the cells used did not come from discarded embryos, the reprogrammed cells were no longer called “embryonic stem cells” but were designated “induced pluripotent stem cells” or “iPS cells” for short.
iPS cells have really lit a fire under the scientific community. What is so exciting about these cells is that, like ES cells, they have the potential to make all the cells of the human body, but unlike ES cells, iPS cells can be made identical to the patient to prevent transplant rejection. Moreover, the derivation of iPS cells is essentially noncontroversial, since no embryos or egg cells are involved.
Recently, however, dark clouds have begun to gather over the iPS cell picture. Reports began to surface that iPS cells actually didn’t seem to behave like ES cells. In one report by scientists at Advanced Cell Technology, Inc., the iPS cell derivatives seemed to age prematurely. Then, at BioTime, we reported that in nearly all of the iPS cell lines we studied, the telomere clock of aging was abnormally shortened-- that is, cells derived from the iPS cells would indeed be prematurely old. However, we showed that it was possible to reset the cellular aging clock back to the beginning of life by sorting through the cells to find ones with sufficient telomerase activity to rewind the clock (Regen. Med. 5(3):345-363). Dr. Homayoun Vaziri (the first author on that paper) and I have recently published a review on the topic available at http://www.futuremedicine.com/toc/rme/5/4 or from PubMed under the title, “Back To Immortality: The Restoration Of Embryonic Telomere Length During Induced Pluripotency.”
Then more recently still, scientists at Harvard reported that iPS cells are abnormal, in that the iPS cells still retain the faint “imprint” of the cells from which they were derived. While this would at worse case likely be a minor problem, it emphasized the need to perfect the iPS process to make it as effective as cloning itself. I describe this as a minor problem because we know that the cells are close enough to normal that they can make a living mouse. In the context of a patient dying for lack of transplantable cells, most scientists believe that some minor abnormalities would be better than nothing at all. But, of course, the goal is to make the perfect cell.
Back to the time machine. The conclusion of all this would be that the egg cell contains molecules, other than the four master regulatory genes commonly used in iPS cell techniques, that makes cloning work so well. Thinking this might indeed be the case, we at BioTime designed ReCyte™ to use a mixture of proteins from egg or sperm-related cells called “EC” cells. We use the proteins derived from the EC cells together with the master regulatory genes of iPS to make what we be believe is currently the optimum reprogramming material to replace the egg cell.
While ReCyte™ is still in development, we believe this proprietary iPS technology may have significant advantages over other techniques. In any event, we believe that it gives us a technology to reset a patient’s cells back to the pristine state of the beginning of life, opening the door to the manufacture of young cells of any type identical to that of the person from whom the original body cells (such as skin cells) were obtained. If that person was suffering as a result of DNA carrying a disease gene such as muscular dystrophy or cystic fibrosis, then that abnormality could be theoretically be corrected in the iPS cells and then those repaired cells could be used to produce cell types free of the disease gene but otherwise identical to the patient. In many diseases like muscular dystrophy, the hope would be that the normal muscle progenitors produced from the iPS cells would be able to proliferate to maintain enough functional muscle to allow a normal life. There are countless other ways the technology could be utilized in medicine.
Off the Shelf vs. Customized Approach:
But what about ES cells? Are they now unnecessary? The answer that I believe most stem cell researchers would agree upon is that both ES and iPS cells will likely be necessary for a long time. The way we see this working is as follows: in order to treat patients afflicted with an acute disease or injury -- that is to say, disease or injuries that occur suddenly like a heart attack, stroke, or skin burn -- physicians will not have time to order cells and tissues to be made from the patient’s own cells through iPS cell technology. iPS cell reprogramming will takes weeks, not days, to deliver a product for a patient. So, we think that for acute applications, existing cells made from existing ES cells will be utilized. We already have banks of clinical grade human ES cells made for this purpose by our subsidiary ES Cell International Pte Ltd in Singapore. Since these cells are not a genetic match to the patient, the cells will either need to be used in treatments with low risk of rejection such as in the brain, eye, or arthritis where the immune system is not as active, or in cases where the cells are not intended to be permanently grafted such as when they are used to target and destroy tumors. These are indeed the applications we and our subsidiaries are targeting first, and the reason we acquired ES Cell International and its clinical grade ES cell bank. For chronic diseases such as heart failure, diabetes, and osteoporosis, where physicians have more time to find a treatment, we think iPS technology will be the source of the ultimate treatment of choice.
The power of human ES cells to generate a platform for the manufacture of all the cell types of the human body, and iPS cell technology to reprogram human cells back to the beginning of life, even resetting the genetic clock of cellular aging, is the foundation of the emerging field of regenerative medicine. Frankly, the power of these technologies stretches the imagination. It is hard to imagine the full potential of the technology, and we do not yet know where all the bumps in the road to the use of these technologies in medicine will reside. BioTime’s aim, and I believe the aim of most researchers around the world, is to accelerate the translation of these technologies from the lab bench to the hospital bedside in the hope that we will one day lift the burden of suffering off our fellow human beings by using these new regenerative medicine technologies to improve the quality of life, and perhaps even to extend life in old age.
July 26, 2010
New developments in stem cell technology offer significant promise for the future of medicine. Human embryonic stem (ES) cells and induced pluripotent stem (iPS) cells are the two sides of the coin of regenerative medicine. Many people ask, “Which of these are the most important, and which holds the future of lifesaving medical therapies?” I believe both will be critical in the coming years. To see why, let me share some of our thoughts in the early years of this technology. By tracing the flow of this history I think it will be possible to bring into focus the big picture.
Medicine has long wished for a means of repairing the hundreds of diverse tissues in the human body. Organ transplantation has become one way of doing this, but its use is severely limited by two things. First, the majority of people in need of tissue never find a compatible donor. The reason for this is that it is quite rare to find organs that are a close match to a given patient. Second, cells and tissues from adult tissues are limited in their ability to regenerate. If they could regenerate, we would simply re-grow amputated arms and legs after they were lost, heart tissue would regenerate after a heart attack, and brain cells would repair the damage occurring in Parkinson’s disease.
The History of ES Cells:
In the mid 1990’s when I was at Geron Corporation, we launched a project to isolate cells we thought could revolutionize this field. The concept was that, theoretically at least, there were cells in the first few days of human life that could form all the cells of the human body. The idea was that if we could capture these cells and cause them to proliferate in the laboratory dish as cell lines, that is to say, cultures where we could expand them into millions and millions of cells without them beginning to differentiate into the cells of the body, we could invent a scalable source of any cell type of the human body. Then we could take these all-powerful stem cells and turn on the molecular switches that would cause them to become anything we needed to make, that is, cartilage for the treatment of arthritis, blood cells for leukemia patients, or cells to produce insulin for diabetics, and so on. We found collaborators in Drs. Roger Petersen at UCSF, James Thomson at the University of Wisconsin at Madison, and John Gearhart at Johns Hopkins University School of Medicine and the race was on to create these cells. As a result of this collaboration, the first human embryonic stem cells were derived in 1998.
Therapeutic Cloning:
Then in 1997 came the advent of animal cloning. Cloning is a technique where the DNA removed from an egg cell is replaced with that of one of the cells of the body of an adult animal. When this is done, amazing things happen. Something in the egg cell changes the DNA of the cell from the body, perhaps a skin cell, and transforms that cell back to the embryonic state wherein the cell has totipotency (the ability to become all the cell types in the body). If this cluster of cells is transferred to a uterus, the cells may attach to begin a pregnancy and perhaps a live born animal, the genetic twin of the animal from which the original cells were obtained.
The first mammal to be cloned in this manner came from a breast epithelial cell, and was named “Dolly” after Dolly Parton. Shortly after Dolly was cloned, some of us proposed using cloning technology in the human species, but not to clone human beings, rather to clone ES cells. This was called “therapeutic cloning” as opposed to “reproductive cloning” (i.e. the cloning of a baby) (Nature Medicine 5(9): 975-977). The promising nature of this technology to us was that this technique could potentially allow medicine to do something that has always been outside its reach; namely to make any type of cell or tissue available in any quantity genetically identical to the patient, thereby obviating transplant rejection for human donors. In addition, we had reasons to believe that cloning technology just might act like a cellular “time machine” to reset the clock of cellular aging by restoring embryonic telomere length (the clock of cellular aging). We showed this was indeed the case, at least in the bovine species in 2000 (Science 288: 665-669).
So the vision was to take a cell from a patient, some cell easy to part with like one from a plucked hair follicle, or a blood cell, then to take that cell back in time using the molecules in the egg cell. Again, the goal was to produce young cells of any kind for old people. The goal never was to clone babies and human beings. We then showed preliminary success in cloning human cells at the earliest stages of life, the cloning of preimplantation embryos (e-biomed: J. Regen. Med. 2: 25-31). However, we were not successful in deriving stem cell lines from these reprogrammed cells (and to my knowledge, no one yet has).
There was, of course, a great deal of controversy over therapeutic cloning. While we said that these early clusters of cells are not yet an individual human being (some of my testimony on that subject can be found at http://michaelwest.org/testimony.htm), others disagreed and vociferously argued that therapeutic cloning, despite any potential benefit to people suffering from degenerative disease, ought to be illegal.
However, the greatest difficulty, in my opinion, was not this ethical controversy over the legal status of preimplantation embryos. Even some theologians have concluded that human life should be considered to begin at about 14 days after fertilization, way beyond the stages of life used in stem cell technology. An example of this would be Norman Ford’s thoughtful analysis in the book “When did I begin?” To me, the real difficulty with therapeutic cloning was the source of the active ingredient in the whole process: the human egg cell. We would need millions of egg cells a year to meet the need of those in need of regenerative therapy. Since young women need to be the source of these cells, a large percentage of these women would need to display a beneficence not yet observed in medical donation.
iPS Cells:
In the years 1999-2005 a number of patent applications were filed on what one might call a “cloning machine.” The idea was to define the molecules in an egg cell that made cloning work and then construct a robotic platform using these molecules to transport a patient’s cells back in time without making embryos or without using egg cells. We at BioTime now call this proprietary process “ReCyte™.” In 2007 the Japanese researcher Shinya Yamanaka and the University of Wisconsin-based researcher James Thomson published the first papers showing that four master regulatory genes could reprogram cells from the human body back to an embryonic state. Since the cells used did not come from discarded embryos, the reprogrammed cells were no longer called “embryonic stem cells” but were designated “induced pluripotent stem cells” or “iPS cells” for short.
iPS cells have really lit a fire under the scientific community. What is so exciting about these cells is that, like ES cells, they have the potential to make all the cells of the human body, but unlike ES cells, iPS cells can be made identical to the patient to prevent transplant rejection. Moreover, the derivation of iPS cells is essentially noncontroversial, since no embryos or egg cells are involved.
Recently, however, dark clouds have begun to gather over the iPS cell picture. Reports began to surface that iPS cells actually didn’t seem to behave like ES cells. In one report by scientists at Advanced Cell Technology, Inc., the iPS cell derivatives seemed to age prematurely. Then, at BioTime, we reported that in nearly all of the iPS cell lines we studied, the telomere clock of aging was abnormally shortened-- that is, cells derived from the iPS cells would indeed be prematurely old. However, we showed that it was possible to reset the cellular aging clock back to the beginning of life by sorting through the cells to find ones with sufficient telomerase activity to rewind the clock (Regen. Med. 5(3):345-363). Dr. Homayoun Vaziri (the first author on that paper) and I have recently published a review on the topic available at http://www.futuremedicine.com/toc/rme/5/4 or from PubMed under the title, “Back To Immortality: The Restoration Of Embryonic Telomere Length During Induced Pluripotency.”
Then more recently still, scientists at Harvard reported that iPS cells are abnormal, in that the iPS cells still retain the faint “imprint” of the cells from which they were derived. While this would at worse case likely be a minor problem, it emphasized the need to perfect the iPS process to make it as effective as cloning itself. I describe this as a minor problem because we know that the cells are close enough to normal that they can make a living mouse. In the context of a patient dying for lack of transplantable cells, most scientists believe that some minor abnormalities would be better than nothing at all. But, of course, the goal is to make the perfect cell.
Back to the time machine. The conclusion of all this would be that the egg cell contains molecules, other than the four master regulatory genes commonly used in iPS cell techniques, that makes cloning work so well. Thinking this might indeed be the case, we at BioTime designed ReCyte™ to use a mixture of proteins from egg or sperm-related cells called “EC” cells. We use the proteins derived from the EC cells together with the master regulatory genes of iPS to make what we be believe is currently the optimum reprogramming material to replace the egg cell.
While ReCyte™ is still in development, we believe this proprietary iPS technology may have significant advantages over other techniques. In any event, we believe that it gives us a technology to reset a patient’s cells back to the pristine state of the beginning of life, opening the door to the manufacture of young cells of any type identical to that of the person from whom the original body cells (such as skin cells) were obtained. If that person was suffering as a result of DNA carrying a disease gene such as muscular dystrophy or cystic fibrosis, then that abnormality could be theoretically be corrected in the iPS cells and then those repaired cells could be used to produce cell types free of the disease gene but otherwise identical to the patient. In many diseases like muscular dystrophy, the hope would be that the normal muscle progenitors produced from the iPS cells would be able to proliferate to maintain enough functional muscle to allow a normal life. There are countless other ways the technology could be utilized in medicine.
Off the Shelf vs. Customized Approach:
But what about ES cells? Are they now unnecessary? The answer that I believe most stem cell researchers would agree upon is that both ES and iPS cells will likely be necessary for a long time. The way we see this working is as follows: in order to treat patients afflicted with an acute disease or injury -- that is to say, disease or injuries that occur suddenly like a heart attack, stroke, or skin burn -- physicians will not have time to order cells and tissues to be made from the patient’s own cells through iPS cell technology. iPS cell reprogramming will takes weeks, not days, to deliver a product for a patient. So, we think that for acute applications, existing cells made from existing ES cells will be utilized. We already have banks of clinical grade human ES cells made for this purpose by our subsidiary ES Cell International Pte Ltd in Singapore. Since these cells are not a genetic match to the patient, the cells will either need to be used in treatments with low risk of rejection such as in the brain, eye, or arthritis where the immune system is not as active, or in cases where the cells are not intended to be permanently grafted such as when they are used to target and destroy tumors. These are indeed the applications we and our subsidiaries are targeting first, and the reason we acquired ES Cell International and its clinical grade ES cell bank. For chronic diseases such as heart failure, diabetes, and osteoporosis, where physicians have more time to find a treatment, we think iPS technology will be the source of the ultimate treatment of choice.
The power of human ES cells to generate a platform for the manufacture of all the cell types of the human body, and iPS cell technology to reprogram human cells back to the beginning of life, even resetting the genetic clock of cellular aging, is the foundation of the emerging field of regenerative medicine. Frankly, the power of these technologies stretches the imagination. It is hard to imagine the full potential of the technology, and we do not yet know where all the bumps in the road to the use of these technologies in medicine will reside. BioTime’s aim, and I believe the aim of most researchers around the world, is to accelerate the translation of these technologies from the lab bench to the hospital bedside in the hope that we will one day lift the burden of suffering off our fellow human beings by using these new regenerative medicine technologies to improve the quality of life, and perhaps even to extend life in old age.
