On the eve of the World Stem Cell Summit in Madison, Wisconsin, Dr. James Thomson offers realistic and sobering words. Interjecting a healthy dose of reality into the unrestrained hyperbole that typically characterizes embryonic stem cell discussions, Dr. Thomson speaks with a tone of authority as well as guarded optimism.

When Dr. Thomson was featured on the cover of Time Magazine in August of 2001, the headline next to his picture read, “The Man Who Brought You Stem Cells”. Indeed, as the world’s first person ever to isolate an embryonic stem cell, first from a rhesus monkey in 1995 and then from a human in 1998, Dr. Thomson is often acknowledged by his peers as “the founder of the field”. Once again leading a major breakthrough when his team announced their success with the development of human iPS (induced pluripotent stem) cells in 2007, Dr. Thomson is revered in stem cell laboratories throughout the world, wherein his name is to stem cell scientists what Einstein’s, Newton’s, and Galileo’s names are to physicists. It may, therefore, come as somewhat of a surprise to many people to discover that Dr. Thomson is considerably more reserved in his enthusiasm for embryonic stem cells and iPS cells than are most advocates.

When asked to predict a timeline for the development of actual therapies which might result from either embryonic stem cells or iPS cells, Dr. Thomson cautiously elaborated upon the technical difficulties that remain and which must still be resolved before such achievements could be realized. Although he said that such therapies might possibly be developed within the next decade, he added that there are still many scientific hurdles to overcome and the public should be prepared for setbacks and disappointment. According to Dr. Thomson, “It’s one thing to make a tissue in culture. It’s another thing to get it into the body and re-establish function. We need to roll up our sleeves and do a great deal of work here, but it’s not going to happen overnight.”

It is well known that embryonic stem cells are inherently problematic, which is why they have never advanced beyond the laboratory stage. Such problems typically include immune rejection, biological contamination, genetic mutation, lack of controllability during differentiation, and the natural tendency of embryonic stem cells to form a particular type of tumor known as a teratoma, among other problems. Additionally, embryonic stem cells are highly controversial for the ethical dilemmas that are inextricably tied to the destruction of embryos, which is required for the derivation of embryonic stem cells. While iPS cells have solved the ethical controversies, to some extent, by avoiding the need for embryonic stem cells entirely, iPS cells are still pluripotent and therefore still do, by definition, cause the formation of teratomas. Clearly, any medical therapy which is given to a human patient should not be worse than the disease or injury that it is meant to treat, which is why anything that causes teratomas cannot be administered as a “therapy” to people until the underlying cellular mechanisms are fully understood and controlled. Such a level of scientific understanding, of such genetically and biochemically complex matters, could take another decade to achieve, if not longer. Meanwhile, exactly how a clinical therapy could be developed from a tumor-causing, pluripotent cell, even if the cell is of non-embryonic origin, such as an iPS cell, is a topic that is not without its own far-reaching ethical controversies.

An embryologist by training, Dr. Thomson is the first to admit that his primary contribution to the world is not so much in the medical profession, nor in the realm of clinical therapies, as it is in the basic science of embryology and developmental biology. Nevertheless, the world turns to him for authoritative direction in medicine and in the treatment of human disease, and for guidance in navigating this brave new world which he played a major role in creating. The public would therefore be wise to heed his prudent and cautionary restraint.

The biotech company BioTime, Inc., and its subsidiary Embryome Sciences, Inc., have recently acquired multiple licenses for stem cell technology patents and their applications, which are now scheduled to be the topics of tomorrow’s conference call. Included within BioTime’s portfolio of patent licenses are proprietary methods for the production of induced pluripotent stem (iPS) cells as well as a number of embryonic stem cell technologies that include the rapid isolation and differentiation of highly purified novel embryonic progenitor cells, with the ultimate goal being the development and commercialization of related products.

BioTime is well known for its development of various surgical technologies that are used in emergency trauma and which include methods of organ preservation, blood plasma expanders, and blood replacement in hypothermic and hypovolemic surgery, among other applications. Through its wholly owned subsidiary Embryome Sciences, Inc., Biotime has recently entered the field of regenerative medicine, in which embryonic stem cell technology is its primary focus.

Among their proprietary technologies thus far, Embryome Sciences utilizes several patents that allow for “vector-free iPS technology”, which is the ability to generate iPS cells without the use of dangerous “vectors”, which include viral vectors such as retroviruses, lentiviruses and adenoviruses, as well as (cancer causing) oncogenes, such as the c-Myc oncogene which has been routinely used in the production of iPS cells and which was found to cause cancer in 20% of the chimeric mice that were utilized in early iPS cell experiements. Embryome Sciences can boast proprietary vector-free technology which avoids such problems, by utilizing iPS transcription factors to transform collateral cells into a cytoplasm that reprograms the patient’s own cells, rather than creating the iPS cells directly by reprogramming adult cells with viral and oncogenic vectors. However, as pluripotent cells, and regardless of how they are produced, iPS cells still do, by definition, cause the formation of teratomas, which are a very specific type of tumor and this unsolved problem remains one of the obstacles yet to be overcome in bringing iPS cells into the realm of clinical therapy. Nevertheless, Embryome Sciences is working to overcome these problems and health risks that are inherent to pluripotent stem cells, whether of embryonic or nonembryonic origin, and Embryome Sciences is hoping to collaborate with other companies on the development and commercialization of related therapies.

Such plans will no doubt be very eagerly addressed in tomorrow’s highly anticipated conference call.

The Anthony Nolan Trust Cord Blood Bank, with facilities in London and Nottingham, is launching a new project that will accommodate the storage of adult stem cells derived from the blood of 50,000 umbilical cords. The project is one of the largest of its kind, and fundraising plans have targeted a goal of 27 million pounds through charitable donations for the projected growth of the organization.

According to the British Minister of Health, Alan Johnson, who opened the center, “For most transplants, the reality is that someone else has to die and donate their organs for another to live. But with bone marrow and cord blood, this is clearly not the case. Bone marrow can be easily and painlessly donated via a single operation. Cord blood offers further potential to change and save lives. Collected, processed and stored at birth, it becomes part of a global life-saving resource. The Anthony Nolan Trust is already acclaimed worldwide, and the impact of the events here today will be felt globally. The complex will help provide a lifeline for thousands complementing the 12 years experience of the NHS Cord Blood Bank, and reinforce the UK’s role as a research center of excellence.”

The institute is planning to match the 400,000 potential donors listed in the Bone Marrow Register of the same charity, which expanded into cord blood stem cells 5 years ago. Of the 50,000 umbilical cord donations that are designated for storage by 2012, 30,000 are planned for research, and the other 20,000 for transplantation. According to Dr. Steve McEwan, Chief Executive of the charity, “The beauty of this new program will not only be to save the lives of hundreds more patients but also to provide researchers the opportunity to develop innovative new treatments using cord blood.”

Prior to expanding into cord blood stem cell research, The Anthony Nolan Trust was focused on leukemia research and bone marrow transplantation. The eponym of the organization was Anthony Nolan, who lived from 1971 to 1979 and who died from a rare blood disorder of genetic origin known as Wiskott-Aldrich syndrome. While the headquarters of the Trust are located in north London, a new facility has just opened on the grounds of Nottingham Trent University, where the company Clean Modules Ltd. has just completed the Cord Blood Cleanroom Centre, where the cord blood stem cells will be processed and stored.

The successful reprogramming of mature, non-stem cell, somatic cells to a more primitive state in which they behave with the same pluripotency as embryonic stem cells, was a major scientific breakthrough that has offered great hope in the field of regenerative medicine. Known as iPS (induced pluripotent stem) cells, these newly formed cells also avoid the ethical dilemmas surrounding embryonic stem cells, since no embryos are required for the generation of iPS cells. However, the conversion of regular somatic cells into iPS cells has been an extremely inefficient process, in addition to dangerous, since the production of these cells involves the use of retroviruses, lentiviruses, adenoviruses and (cancer causing) oncogenes, none of which are allowable for clinical use, and all of which are specifically prohibited by the FDA (Food and Drug Administration) and are grounds for disqualification from the FDA approval process of medical therapies. Furthermore, the precise molecular, genetic and biochemical mechanisms of cellular reprogramming that are at work in the production of iPS cells are still not yet fully understood.

Two independently published papers, however, now signify further progress in the field. A team led by Dr. Konrad Hochedlinger of the Harvard Stem Cell Institute, and another team led by Dr. Rudolf Jaenisch of the Massachusetts Institute of Technology and the Whitehead Institute, have both published findings which corroborate each other’s work.

Dr. Hochedlinger’s team was able to generate iPS cells with a pluripotency similar to that of embryonic stem cells, not by using the viral and oncogenic vectors that have been previously used, but instead by using the drug doxycycline for reprogramming of the cells. Perhaps of greatest importance, however, was the discovery that after the “primary” iPS cells were allowed to differentiate into mature cells, the researchers then re-exposed the cells to doxycycline a second time, which induced the production of a “secondary” group of iPS cells that was generated even more quickly and efficienty than the “primary” group that was produced after the first exposure.

Dr. Jaenish and his team also addressed the idea of generating a secondary round of iPS cells, in a separate paper wherein they describe experiments in which they were able to derive secondary iPS cells by using doxycycline-inducible transgenes. According to Dr. Jaenisch, “The drug-inducible system we describe represents a novel, predictable, and highly reproducible platform to study the kinetics of iPS cell generation. Furthermore, the genetic homogeneity of secondary cells makes chemical and genetic screening approaches to enhance reprogramming efficiency or to replace any of the original reprogramming factors feasible.” Dr. Hochedlinger adds, “The secondary system will enable chemical and genetic screening efforts to identify key molecular constituents of reprogramming, as well as important obstacles in this process, and will ultimately lend itself as a powerful tool in the development and optimization methods to produce human iPS cells.”

Both research teams confirmed that generation of the secondary group of iPS cells is faster than the generation of the primary group, although the precise time that is involved depends upon the types of skin cells that are used. Human keratinocytes, for example, were found to take approximately 10 days for production, whereas fibroblasts required several weeks. According to Dr. Hochedlinger, “The fast kinetics of reprogramming observed for keratinocytes suggests that these cells would be useful for development and optimization of methods to reprogram cells by transient delivery of factors.”

One problem still remains, however, which is the ability of all iPS cells to cause teratomas, which is a specific type of tumor. By formal definition, any cell which is “pluripotent” is capable of forming a teratoma, and if a cell cannot form a teratoma then it is recognized as not being pluripotent. Exactly how pluripotency in a cell may be turned on or off, like a switch, or controlled to the extent that anyone can guarantee, with 100% certainty, that the cell will not cause tumors when administered to human patients, remains to be seen.

Meanwhile, the ability to produce a “secondary” round of iPS cells, more quickly and efficiently than the first round, via a second exposure to doxycycline, represents a significant and important discovery, as scientists advance one step further along the path of elucidating the complex cellular mechanisms that are at work in reprogramming and differentiation.

The recipients of the coveted Shaw Prize this year include Sir Ian Wilmut and Dr. Keith Campbell of the U.K., and Dr. Shinya Yamanaka of Japan, all of whom shared the million-dollar life sciences award. According to an official statement released by the organizers of the event, “Based on these discoveries, animal experiments by others have already shown that it was possible to cure mouse models of sickle cell anemia and Parkinson’s disease.”

Although Dr. James Thomson of the University of Wisconsin at Madison is widely recognized as the first to conduct iPS cell procedures on human skin cells, Dr. Yamanaka of Kyoto University preceded Dr. Thomson’s work by performing the first iPS procedure on mouse fibroblasts in 2006.

Sir Ian Wilmut has often been in the news lately, not so much for his cloning of Dolly the Sheep as for his statement that he is abandoning the field of cloning in order to shift his focus to adult stem cells, which he believes merit the greatest attention.

Established in 2002 by a Hong Kong film producer and philanthropist, the Shaw Prize is actually three separate prizes, which are awarded for outstanding achievement in the life sciences, the mathematical sciences, and astronomy. Each of the awards consists of one million dollars in cash.

The embryonic stem cell company, Advanced Cell Technology (ACT), of Worcester, Massachusetts, has announced that it plans to vacate its Charleston facility and it also will not renew its lease on a California research center. The announcement comes as part of the company’s plan to eliminate $5 to $6 million from its annual operating budget, in the face of escalating debt.

According William Caldwell IV, CEO, “Near-term funding continues to be our major challenge. The company plans to spend its remaining cash on the most advanced clinical programs.” Other executives in the life sciences who were interviewed attribute ACT’s financial troubles to inflated and unsubstantiated claims regarding embryonic stem cells, which included early reports of cloned human embryos and the embryos of endangered species which later proved to be unverifiable.

In an S.E.C. filing in July of this year, ACT reported $1 million in assets and $17 million in liabilities. According to a company representative, ACT attributes its own financial problems to a heavy dependence on “emerging and sometimes unproven technologies” within an “ethically sensitive and controversial” broader context.

Last month, ACT received $250,000 in initial payment for a licensing agreement with Embryome Sciences, a subsidiary of BioTime, Inc, currently directed by Michael West who was formerly the CEO of ACT.

“Potency” is one of the most important properties of a stem cell, and a measure of the cell’s ability to differentiate into various types of tissue. As one of the highest forms of potency, second only to totipotency, “pluripotency” is a coveted feature reserved only for embryonic stem cells and iPS (induced pluripotent stem) cells. Safety and efficacy are also of the utmost importance, however, and pluripotency is well known to be associated with specific risks, especially the formation of teratomas, which are a unique type of tumor.

In the latest issue of the journal Nature, two leading scientists in the stem cell field, Drs. Rudolf Jaenish and Christopher Lengner, both of the Massachusetts Institute of Technology, offer a striking visual illustration that compares the pluripotency of embryonic stem cells with the pluripotency of laboratory-generated cells that are derived from non-embryonic sources, such as the iPS (induced pluripotent stem) cells that are reprogrammed from adult skin cells.

Embryonic stem cells are known not only for the ethical dilemmas that they present, but also for a long list of scientific problems which include difficulty of isolation, biological and chemical contamination, genetic mutation, a lack of controllability during differentiation and, by definition, the ability to form those very specific types of tumors which are known as teratomas. Indeed, as depicted in Drs. Jaenish’s and Lengner’s illustration, teratoma formation remains one of the universally accepted criteria by which pluripotency is defined and empirically determined, even for cells which are not of embryonic origin, such as the iPS cells. Created through such techniques as nuclear transfer, genetic reprogramming and cellular fusion, ordinary adult somatic cells which are not stem cells have been induced to behave with a pluripotency that resembles that of embryonic stem cells, but which circumvents the ethical controversy surrounding embryonic stem cells, by avoiding the use of embryos altogether. These cells, such as the iPS cells, may have solved the ethical controversy, by entirely circumventing the need for embryonic stem cells, but these newly derived pluripotent cells do not solve the medical problems and risks that are associated with teratoma formation, since such cells, by definition, still cause the formation of teratomas and this is still how pluripotency is defined and identified. If a cell forms a teratoma, then it is recognized to be a pluripotent stem cell – whether of embryonic origin or of non-embryonic origin, such as the iPS cells.

Adult stem cells, by contrast, do not form teratomas since they are not pluripotent but instead are, at best, “multipotent”, and as such are well understood to be “lineage-restricted” in their differentiation ability. While such a lack of pluripotency has, in the past, been erroneously seen as an undesirable feature of adult stem cells, it is now recognized as being highly advantageous for a number of reasons which include greater controllability in the differentiation process and no risk of teratoma formation, among other advantages of adult stem cells.

The entire fields of tissue engineering and regenerative medicine are founded upon properties of cellular potency, but not all stem cells are created equal, and a wide spectrum exists across which their properties may be ranked. The specially featured illustration by Drs. Jaenish and Lengner in the latest issue of Nature is already recognized as offering a new and updated set of guidelines for scientists in the field, and a free copy of the illustration may be downloaded at the journal’s website, www.nature.com.

The Chairman and CEO of NeoStem, Robin Smith, M.D., MBA, has been invited to present a talk on the growing phenomenon known as “medical tourism”, and its implications, at the upcoming World Stem Cell Summit to be held in Madison, Wisconsin from September 21st through the 23rd.

In 2007, approximately 750,000 Americans traveled abroad in search of medical care, and this number is projected to reach 6 million by 2010. Similarly, of all international travelers who leave their home country to find medical care elsewhere, approximately 40% of those people are non-Americans who travel to the United States for medical treatment, according to a McKinsey report that was issued in May of 2008. Medical companies and clinics that are strategically located within major destination cities within the U.S. are therefore likely to profit from this growing global trend toward “medical tourism” – especially in the field of stem cells.

According to Dr. Smith, “We have already begun to see international interest as evidenced by a collection performed at a NeoStem center in New York last week on an individual who lives in Dubai. NeoStem believes that individuals in increasing numbers will seek safe and effective stem cell therapies abroad that are not yet approved in the United States and many important clinical advances will be in hospitals and clinics outside the United States. We believe that we could gain value from this by including medical tourism in the company’s future business strategy.”

As the first company to offer autologous adult stem cell collection and banking services to the general adult population, NeoStem works exclusively with adult stem cells, not embryonic stem cells. NeoStem collects adult stem cells from peripheral blood, thereby avoiding bone marrow aspiration collection techniques which must usually be performed under general anesthesia. NeoStem has also entered into a number of R&D projects through the acquisition of licensed technology that identifies and isolates VSELs (very small embryonic-like stem cells).

Since adult stem cells are already being used in clinics around the world for the treatment of a wide variety of diseases and injuries, and since a number of proprietary adult stem cell products are already in clinical trials in the U.S., it would seem to be only a matter of time before FDA approval is attained and such adult stem cell therapies are legally and widely available within the United States. When that happens, the U.S. could become the adult stem cell “Mecca” of the world.

A team of researchers led by Dr. Douglas Melton of the Harvard Stem Cell Institute, in collaboration with researchers at the Howard Hughes Medical Institute, have successfully transformed mature cells in mice into a different type of cell.

The research, which was published today in the online journal Nature, involves the reprogramming of a cellular “identity switch”, which is a type of master control for determining which genes in the cell are activated and which remain inactive. The findings are the first of their kind to be conducted in vivo, with the transformation of ordinary pancreatic cells into the more specialized beta islet cells, which are the cells that produce insulin.

Such research represents a further step in the ongoing effort by many scientists to avoid embryonic stem cells and their ethical dilemmas, by working with pluripotent stem cells from non-embryonic sources. Earlier studies with iPS (induced pluripotent stem) cells, for example, used ordinary skin cells from adults that were reprogrammed into a more primitive state, from which they could then be directed to develop into various types of tissue, at least theoretically. One of the problems encountered with the iPS cells, however, is the difficulty of controlling their differentiation into the desired, specialized tissue. This latest discovery, however, changes a mature cell into another mature cell without having to revert back to a primitive cell as an intermediate stage.

Using mice in which the beta islet cells had been destroyed, Dr. Melton’s team injected the pancreas of the mice with a viral “vector” that delivered 3 genes into the ordinary pancreatic cells, which 3 days later were found to have been converted into the insulin-producing beta islet cells. After a week, over 20% of the cells had begun producing insulin. The newly formed cells were identified as beta islet cells both morphologically (in structure) as well as functionally. According to Dr. Richard Insel, executive vice president of research at the Juvenile Diabetes Research Foundation, this research represents “an amazingly efficient effect”, much more so than that seen from iPS cells thus far.

Dr. Melton has a personal interest in diabetes, and has been a leading researcher in the field since 1993, when his infant son was diagnosed with Type 1 diabetes. However, scientists are quick to observe that these findings have a wide range of implications which extend far beyond diabetes. Researchers at Stanford, for example, are currently studying applications of the same procedure with liver cells. Indeed, the findings mark an important achievement in understanding the molecular signals that are involved in the reprogramming of cells, which is relevant to the treatment of virtually every type of disease.

Following experiments with mice, Stanford University scientists have announced that stem cell therapies which use human embryonic stem cells (hESCs) have a high probability of failing because of immune rejection. In these studies, mice that were injected with hESCs exhibited an immune response which is at least as severe as that triggered by organ transplantation. Consequently, all the transplanted stem cells were killed by the immune system within a week. The Stanford researchers used molecular imaging technology to monitor the hESCs after injection, which revealed that the hESCs began dying within a week of injection and were completely dead by 10 days. When more hESCs were subsequently injected, they were found to die much more quickly, within 2 to 4 days, due to the already fully activated level of the immune system defense response. Even when the animals were given tacrolimus and sirolimus, two mediations that are commonly used to suppress an immune response, the hESCs lasted 28 days before dying but were still rejected and killed by the immune system. Additionally, in all cases, the overall health of the animals continued to deteriorate, and the researchers were not able to determine any benefit from an increase in time before all the hESCs were eventually destroyed.

The U.S. FDA (Food and Drug Administration) has not approved the use of hESCs as a medical therapy, primarily because of the danger of teratomas, which are a well established risk of hESCs. A teratoma is a specific type of tumor which contains cells from all 3 germ layers of the body, which have often differentiated into specialized tissue such as teeth, hair and organs, and which therefore make these tumors particularly hideous and dangerous. The ability of embryonic stem cells to form teratomas is, in fact, the defining trait of embryonic stem cells, and the ability of a cell to form a teratoma remains the universal laboratory test by which embryonic stem cells are identified: namely, if an unknown cell is found to form a teratoma in the laboratory, then it’s an embryonic stem cell, whereas if it doesn’t form a teratoma, then it’s not an embryonic stem cell. Teratoma formation, however, is certainly not the only risk posed by embryonic stem cells, and once again we are now reminded of the dangers of immune rejection that are inherent in embryonic stem cells. Adult stem cells, by sharp contrast, do not pose any risk of teratoma formation, and some types of adult stem cells, such as mesenchymal stem cells (MSCs), are known to be “immune privileged”, meaning that they do not trigger an immune response.

According to Dr. Joseph Wu, a Stanford radiologist who led the recent research, these findings, which reveal such a strong immune rejection of embryonic stem cells, constitute “a reality check”.