The recent merger of two high-profile biotechnology companies, Geron Corporation of Menlo Park, California, and the Roslin Institute's Roslin Bio-Med of Midlothian, Scotland, could give a jump-start to what is being called "regenerative medicine," the replacement of tissues and organs damaged by degenerative diseases and age.
As Geron Bio-Med, the two firms - one having developed Dolly the sheep via nuclear transfer, and the other having isolated telomerase and human embryonic stem cells - plan to develop unlimited supplies of autologous cells, tissue, and organs for transplantation. Such therapy could address diseases including cancer, Alzheimer's, macular degeneration, diabetes, and congestive heart failure.
Ian Wilmut, Dolly's creator, acknowledged that the six-year, $20 million collaboration is "a very ambitious research project." Individually, their three pioneering technologies of nuclear transfer, human pluripotent stem cells, and telomerase expression "have the potential to significantly improve our ability to treat and even cure many diseases," Wilmut said. "Together, that potential is enhanced dramatically," he added.
The marriage of Geron and Roslin Bio-Med means that Wilmut's team has the time and resources to focus on basic research necessary to better understand cell dedifferentiation in nuclear transfer, as well as cell differentiation from pluripotent stem cells, the process needed to prompt differentiation into kidney cells rather than heart cells, for example. Geron Bio-Med's ultimate goal is to be able to generate an unlimited supply of cells, tissues, and organs for a wide range of degenerative diseases - cancer, Parkinson's disease, cardiovascular diseases, and diabetes, to name a few. This transplant material would be derived from the patients themselves, who would therefore require no immunosuppressive drugs.
In the Beginning
With the birth of Dolly in February 1997, Wilmut and his Roslin Institute team made the first breakthrough in reprogramming an adult differentiated animal cell through nuclear transfer, or cloning. But Roslin is more than Dolly's home. It is one of the world's leading centers for theory and application of molecular and quantitative genetics of farm animals. Besides holding a strong intellectual property position in nuclear transfer technology, in 1998 Roslin licensed the technology to PPL Therapeutics to produce therapeutic proteins in the milk of transgenic ruminants and rabbits, and for the modification of milk for nutraceutical use. Also in 1998, the Roslin Institute established Roslin Bio-Med, with backing from the European venture capital firm 3i, as a commercial subsidiary of the Roslin Institute to commercialize nuclear transfer technology.
Enter Geron, which has enjoyed a high media profile (and accompanying stock leaps) since January 1998, when it published a study in Science demonstrating that it could reactivate telomerase in normal cells by means of gene transfer, enabling cells to divide indefinitely. [1] In March of that year, it reported that such "immortalized" cells did not become cancerous even though they shared the characteristic of indefinite longevity. [2] Finally, in November 1998, Geron made its third public announcement: two of its researchers, James Thomson of the University of Wisconsin at Madison and John Gearhart of Johns Hopkins University in Baltimore, had concurrently isolated and cultured human embryonic stem cells which, in theory, could become any type of somatic cell. [3]
Dream Team?
As far as Wilmut is concerned, "the greatest gain from the Dolly experiments is not that animals can be produced by nuclear transfer, but its potential applications for human health. For example, one could take a cell from a child ill with leukemia, transform it, expand it, and return it to the child to cure the disease."
The time frame necessary to develop customized, autologous cells and organs for transplantation could be as long as 20 years, Wilmut said. Thomas B. Okarma, Geron's vice president of cell therapies, is more optimistic, and estimates that it may be as short as 10 years.
Few biotech companies believe they can afford the "luxury" of undertaking such basic research, which requires long-term commitment and funding, yet holds such great promise for the far future. But Geron Bio-Med also plans for the more immediate future, with more realizable projects that should generate revenue over the next few years.
"We plan to use the three technologies to produce cloned, transgenic herds of knockout pigs that can be used in xenotransplantation," said Okarma. "We will be able to generate an unlimited number of genetically identical animals which do not carry the galactosyltransferase gene and thereby would not be rejected by a human recipient," he added.
The new company also plans to use the technologies to produce disease-resistant farm animals, and is seeking corporate partners for this application. Most immediately, Geron Bio-Med will develop cloned cell lines for use in drug screening and toxicology.
Not Alone
It is in these nearer-term projects that Geron Bio-Med will most likely meet competition. Numerous other biotech companies are already vying for the xenotransplanation and cloned transgenic animal markets, with products in late-stage preclinical trials, and a few in early clinical trials. None have access, however, to all three technologies, and it is unclear whether that is crucial even for the short-term. BioTransplant, of Charlestown, Massachusetts, is employing a number of methods (without nuclear transfer) to rid pigs of immunological barriers for transplantation.
Alexion Pharmaceuticals of New Haven, Connecticut, is using genetic engineering with transgenic pigs to express human complement proteins to rid them of certain sugars that produce complement-mediated rejection in recipients. "We reported in late April that such transplanted pig cholinergic neurons used in an animal model of Alzheimer's disease, restored cognitive ability and memory in rodents," said Alexion president Leonard Bell. He expects to enter the clinic within one to two years in either Alzheimer's or Parkinson's disease - or both.
The company that most closely resembles Geron Bio-Med is Advanced Cell Therapy (Worcester, Massachusetts). It is using a different type of nuclear transfer (with dividing cells, rather than the Wilmut team's quiescent cells) with cells from humans and animals, rather than embryonic stem cells, to avoid ethical controversy, said chief scientist Jim Robl. Advanced Cell Therapy president and CEO Michael West was Geron's founder.
Numerous other biotech companies are working with differentiated stem cells - neural, hepatic, mesenchymal, and pancreatic - to develop cell therapies useable in the next few years. Osiris Therapeutics in Baltimore is using mesenchymal stem cells to develop products already in trials: Stromagen is in phase I as support for recovery from chemotherapy, and it has a large partnership with Novartis for cartilage development for osteoarthritis and osteoporosis. Daniel R. Marshak, senior vice president of research and development, commented that his company had veered away from using embryonic stem cells because of their controversy. "In addition, most people in the field agree that embryonic stem cells are a long way from being translated into products."
"Using totipotent stem cells as the basis for developing differentiated cells and tissues is way far in the future," according to Irving Weissman, who isolated the hematopoietic stem cell in the early 1990s and is professor of pathology and developmental biology at Stanford University. "We don't know anything about the pathways of differentiation," said Weissman, who was a founder of SyStemix (Palo Alto, California) and StemCell (Richmond, California), a subsidiary of CytoTherapeutics. SyStemix is working with hematopoietic stem cells, and StemCell has patents on neural and pancreatic stem cells. Weissman and others are skeptical about Geron Bio-Med's ability to go the distance, and are banking on their own efforts to contribute to "regenerative medicine" in the next few years.
Geron Bio-Med is not worried, however. "In the past few months, we have made strides toward understanding some of the mechanisms necessary for certain types of cell differentiation," Okarma said. "One of our first scientific targets, understanding what factors influence the nucleus to differentiate, could be realizable soon. Being able to mimic that could take longer," added Wilmut. But for this new company, the potential gains are worth the gamble.
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