The U.S. Patent and Trade Office has awarded patent # 7,517,686 to scientists at the Blasticon Biotechnologische Forschung GmbH in Germany for their invention of a method by which dedifferentiated, programmable stem cells of monocytic origin are created. The invention also describes pharmaceutical applications and methods for differentiating the stem cells into target cells and tissue.

A type of white blood cell with distinct immunological properties, monocytes are conveniently obtained from peripheral blood which is easily drawn from a simple intravenous blood collection. Originally produced in the bone marrow from hematopoietic precursor cells known as monoblasts, monocytes play a central role in immune and inflammatory responses and are routinely measured for diagnostic purposes in a complete blood count.

The patent description includes methods for isolating monocytes from human blood, culturing the monocytes in a medium containing the cytokine and cellular growth factor M-CSF (macrophage colony stimulating factor) as well as IL-3 (interleukin-3), from which the dedifferentiated programmable stem cells are found to express the CD14, CD90 and CD123 antigens. As the authors explain in the “background” of their invention, “The use of embryonic stem cells has been the subject of extensive public discussion, especially in Germany, and is regarded as extremely problematical. Besides the ethical and legal problems connected with embryonic stem cells, the therapeutic use of such cells also comes up against difficulties. By nature, embryonic stem cells are obtained from donor organisms, which are heterologous vis-a-vis the potential recipients of differentiated cells or tissue (hereafter referred to as somatic target cells or target tissue) developed from these cells. It is therefore to be expected that such target cells will trigger an immediate immunological response in the potential recipients in the form of rejection.” By contrast, the derivation of pluripotent stem cells from autologous monocytes that are collected from ordinary adult peripheral blood circumvents such difficulties.

As the authors further explain, “the foreseeable development of the age and disease profile of the population in the western world is decisive, leading to the expectation of a drastic turning point in the next 10 years in the health and care sector of the western European population, including the USA and Canada. In the Federal Republic of Germany alone, the demographic development suggests a 21% growth in population in the 45 to 64 year-old age group by 2015, and a 26% growth in the over-65 age group. This is bound to result in a change in patient structure and in the spectrum of diseases requiring treatment. Predictably, diseases of the cardio-circulatory system (high blood pressure, myocardial infarction), vascular diseases due to arteriosclerosis, and metabolic diseases such an diabetes mellitus, diseases of liver metabolism, kidney diseases as well as diseases of the skeletal system caused by age-related degeneration, and degenerative diseases of the cerebrum caused by neuronal and glial cell losses will increase and require innovative treatment concepts. These facts explain the immense national and international research and development efforts by the specialists involved, to obtain stem cells which can be programmed into differentiated cells typical of tissue (liver, bone, cartilage, muscle, skin etc.). The problem underlying the invention therefore resides in making available adult stem cells, the generation of which gives rise to no ethical and/or legal problems, which are rapidly available for the planned therapeutic use in the quantities required for this, and at justifiable production costs, and which, when used as ‘cellular therapeutics’ give rise to no side effects – or none worth mentioning – in terms of cellular rejection and induction of tumors, particularly malignant tumors, in the patient in question.”

Within the claims of their invention the scientists propose methods for treating a number of diseases which include cirrhosis of the liver, pancreatic insufficiency, acute and chronic kidney failure, hormonal underfunctioning, cardiac infarction, pulmonary embolism, stroke and skin damage. Additionally, implantable prostheses for various anatomical structures such as cardiac valves and vessel prostheses as well as bone and joint prostheses are also described. Such claims are possible since the invention describes the dedifferentiation and redifferentiation of the monocytes into a variety of target cell and tissue types which include neuronal precursor cells, neurons and glial cells, endothelial cells, adipocytes (fat cells), hepatocytes (liver cells), keratinocytes (skin cells), and insulin-producing (pancreatic beta islet) cells. The authors further describe the coexpression of albumin and the monocyte-specific antigen CD14 in the hepatocytes, as well as the in vivo use of the cells in an animal model.

As the authors explain, “The generation of the stem cells according to the invention is completely harmless to the patient and – in the case of autologous use – comparable to own blood donation. The quantity of stem cells required for the usual therapy options can be made available cost-effectively within 10 to 14 days after the blood is taken. In addition the cell product provided for the therapy, in the case of autologous use, does not give rise to any immunological problem in terms of cell rejection, as cells and recipient are preferably genetically identical.”

The claims of the invention also include an absence of the threat of cancerous malignancy, since, as the authors describe, “The stem cells according to the invention have also proved to be risk-free in animal experimentation and in culture with regard to giving rise to malignancy, a result which is only to be expected due to the cell of monocytic origin, from which the stem cells according to the invention derive.”

Unlike the iPS (induced pluripotent stem) cells that are often in the news and which carry a number of risks not only because of their ability to form teratomas (tumors) but also because of the oncogenes (cancer causing genes) with which they are produced, these new stem cells of monocytic origin are created without oncogenes through a very different dedifferentiation process. The authors describe genetic transfection of the cells with the FAH (fumarylacetoacetate hydrolase) gene, and transfection with “multidrug resistant genes” such that “extended radical chemotherapy can be made possible in the case of malignant diseases by corresponding hematopoietic reconstitution, or radiation resistance can be produced.”

Even though monocytes are ordinarily collected and separated from whole blood, they could also be alternatively obtained directly from organs, if necessary, such as in the case of contraindicating blood conditions such as anemia or leukemia, for example.

Although the patent was awarded today, the patent application was originally filed on November 21st of 2005.

Led by Dr. Patrick Lee of the Department of Microbiology and Infectious Diseases at the University of Calgary, scientists have discovered that the commonly occurring reovirus can selectively target and destroy the cancerous stem cells that cause breast cancer. Additionally, the reovirus also exhibits other beneficial cellular and molecular action by stimulating the body’s immune system and natural anti-cancer defense mechanisms.

It was over a decade ago, in 1998, when Dr. Lee originally announced his discovery that the reovirus (an acronym for Respiratory Enteric Orphan virus) can kill cancer cells. Now, the discovery has been extended specifically to breast cancer stem cells, which are the “master cells” gone awry and which consequently generate cancer cells in the breast.

As Dr. Lee explains, "You can kill all the regular cancer cells in a tumor, but as long as there are cancer stem cells present, disease will recur." Indeed, it has taken the medical profession awhile to appreciate the full significance of cancer stem cells and the importance of eliminating these stem cells in any clinical cancer treatment. Cancer stem cells are difficult to kill, however, and are often highly resistant to standard chemotherapy and radiation treatments, which accounts for the low success rates of chemotherapy and radiation. As Dr. Lee further explains "Cancer stem cells are essentially mother cells. They continuously produce new cancer cells, aggressively forming tumors even when there are only a few of them. Cancer stem cells just keep churning out new cancer cells. No matter how many cancer cells you kill, you can’t stop the cancer until you kill the stem cells." Even if the cancer stem cells themselves remain in very small numbers, they can still produce new tumors, in large numbers. Without eliminating the cancer stem cells in their entirety, the cancer that is produced by the stem cells can never be fully eliminated. The only way to "cure" any particular type of cancer, therefore, in the absolute sense of the word, is to get to the root of the problem and eliminate the cancer stem cells.

Now, in an effort to do exactly that, scientists are looking at ways of utilizing the reovirus as a virus-based anti-cancer therapy, which is currently being tested in 10 clinical trials, 4 in the U.K., and 6 in the U.S., under the name “Reolysin”, which is marketed by the Canadian company Oncolytics Biotech. Although the current issue of the journal Molecular Therapy describes a study in which the reovirus is utilized for the specific treatment of breast cancer, the study complements and corroborates a number of other clinical and preclinical studies in which the reovirus is also utilized to treat other forms of cancer as well.

The mechanism-of-action of the reovirus is particularly advantageous as a cancer therapy, since the reovirus has been found to preferentially replicate in Ras-activated cancer cells, thereby causing virus-mediated cell death. Additionally, scientists have discovered that the tumor antigens generated by viral oncolysis (the destruction of tumor cells) may “educate” the immune system to recognize and kill similar tumor cells in the future. Based upon principles such as these, the proprietary anti-cancer product Reolysin has been formulated to replicate specifically in tumor cells that bear an activated Ras pathway, and which are therefore also deficient in their ability to activate a natural anti-viral response as mediated by PKR (protein kinase R) activity, which is present in normal cells but absent in tumor cells with activated Ras pathways, since normal cells do not possess activated Ras pathways. As the tumor cells die, the progeny viral particles in turn spread to neighboring cells, a process which in turn triggers the continuous cycle of infection, replication and cell death – a cellular cycle that repeats itself until there are no more tumor cells remaining which bear the activated Ras pathway.

The activated Ras pathway is one of the most common genetic defects that are known to predispose an individual to developing cancer, and it is believed that the activation of mutations in Ras, as well as in upstream elements of Ras, may be implicated in more than two-thirds of all human cancers. Scientists therefore hope that Reolysin may represent a novel treatment not only for Ras-activated tumor cells but also for other types of cellular proliferative disorders.

Reovirus is commonly known to inhabit the human respiratory and bowel systems, being naturally found in sewage and water supplies, but it is nonpathogenic. Its anti-cancer properties were first established after the reovirus was found to replicate so easily within Ras-activated cancer cell lines. According to Dr. Lee, “The cancer cell environment lets the virus uncoat and start reproducing more quickly than it can in normal cells. The rapidly growing mass of virus particles ruptures the infected cancer cell, releasing virus particles to infect other cancer cells in the body. So theoretically it can even kill cancers that have metastasized.” Dr. Lee adds, "We suspected that reovirus might be effective against cancer stem cells, because we have shown time and again how well it destroys regular cancer cells."

Unlike most cancer studies, which use cancer cell lines that have been developed exclusively for laboratory use, Dr. Lee’s study utilized fresh breast cancer tissue that was derived from a live patient. As Dr. Lee explains, "Refining this two-pronged approach to killing cancer is our next step. We are taking advantage of the natural characteristics of reovirus and the immune system itself to create a powerful virus-based anti-cancer therapy."

Additionally, Oncolytics Biotech has developed a clinical program which includes human trials that use Reolysin by itself and also in combination with radiation and chemotherapy. Headquartered in Calgary, Alberta, Oncolytics Biotech was founded in 1998 for the specific purpose of developing pharmaceutical cancer therapies that are based upon the oncolytic properties of the reovirus. Thus far, Oncolytics Biotech has concluded nine human Phase I/II clinical trials in the U.K. and the U.S. which have yielded positive interim data for lung, liver and nodal metastatic disease. Additionally, Reolysin is in Phase II/III clinical trials for patients with refractory head and neck cancers, and Oncolytics is currently in a collaborative agreement with the U.S. National Cancer Institute for the design of multiple clinical trials. Independent preclinical studies have also demonstrated that the reovirus can destroy cancers of the brain, ovary, prostate, breast and colon, in addition to melanoma and lymphoma.

Another important variable is the transcription factor p53 which normally plays a role in tumor suppression. According to Dr. Lee, “Learning how p53 works and why it loses its protective function in cancer could well lead to a cure.”

In the United States, cancer is responsible for one out of every four deaths, ranking second only to cardiovascular disease in prevalence. Approximately 1.4 million people in the U.S. were diagnosed with cancer in 2008 alone, more than half of whom are expected to die from the disease. The probability of developing cancer at some point in life is approximately 50% (or one out of every two people) for the average U.S. male, and approximately 33% (or one out of every 3 people) for the average U.S. female. In 2007 the U.S. National Institutes of Health estimated that the overall annual cost for all types of cancers combined in the United States was $219.2 billion, of which $89 billion was directly attributable to medical expenses while the remaining $130.2 was attributable to lost productivity

Dr. Patrick Lee is a founding member of the Beatrice Hunter Cancer Research Institute at the Dalhousie University Medical School in Halifax, Nova Scotia.

Molecular Therapy is a journal of the American Society of Gene Therapy.

Researchers in China have demonstrated in female mice that ovaries produce new eggs throughout adulthood, which can then develop into offspring. The discovery overturns a previous theory which was applied not just to humans but to all mammals in general and which held that female mammals are born with a finite number of oocytes (the female gametocyte that develops into ova, or eggs), a number which cannot increase throughout life. Now, however, there is evidence to indicate that the number of oocytes can, and does, increase throughout the lifetime of the female. Apparently, it would seem as though the previous theory did not take into account the concept of a stem cell.

In a study led by Dr. Ji Wu, a professor at Shanghai Jiao Tong University, the researchers isolated female germline stem cells (FGSCs) from adult mice and also from five-day-old infant mice. Even after being cultured several times, regardless of age, all the FGSCs were still found to proliferate. Most interestingly, the adult FGSCs continued to produce new oocytes and thereby restored fertility when transplanted into the ovaries of female mice who were previously infertile, and who subsequently gave birth to normal mice.

According to Dr. Paul Sandberg, professor of neurosurgery and director of the University of South Florida Center for Aging and Brain Repair in Tampa, “These stem cells are continuous. They were still around through life and actually transformed to make oocytes. Then they were transplanted into infertile females and produced offspring.”

Scientists now hope that applications of this discovery could be extended to the development of a new stem cell therapy for infertility in human females. Some researchers are cautious of such high hopes, however, such as Dr. George Attia, associate professor of reproductive endocrinology and infertility at the University of Miami Miller School of Medicine, who states, “If it would ever come to fruition in humans, I really don’t know. It’s far, far out there.” As Dr. Darwin J. Prockop, director of the Texas A&M Health Science Center College of Medicine Institute for Regenerative Medicine, adds, “There are too many steps, too many things could go wrong.”

Nevertheless, the idea that female mammalian babies are born with all the ova that they will ever have in their entire lives – a theory which never made much sense to a lot of people – has now been disproven. As with spermatocytes, the male gametocytes from which spermatozoa develop, there is now evidence to indicate that oocytes in females are also replenished throughout life.

The biotech company Cryo-Cell International announced in its earnings report today that its net income for the first quarter of the 2009 fiscal year was $536,000, a significant increase from its net loss of $247,000 in the first quarter of the 2008 fiscal year. Total revenue as of February 28 was reported at $3.9 million for the year, with approximately $5.7 million in available cash, cash equivalents, marketable securities and other investments. By the end of the quarter, the company no longer had any long-term debt.

According to Mercedes Walton, chairwoman and CEO of Cryo-Cell, the company was able to reduce administrative, marketing and sales expenses over the previous year, while prospective clients increased 94%. Licensee income for the first quarter totalled approximately $338,000, compared to approximately $183,000 for the first quarter in 2008. As Ms. Walton explains, “We are clearly encouraged by Cryo-Cell’s performance in the first quarter of fiscal 2009, which represents the company’s second consecutive quarter of recurring profitability. Despite the weakness in the U.S. economy and its impact on discretionary consumer spending, Cryo-Cell is pleased to deliver first quarter 2009 earnings of $536,000 and gross margins of 71%. Cryo-Cell continues to make substantial progress both strategically and operationally. Our momentum is strong, and we anticipate that shareholder value will increasingly reflect the company’s solid performance and growing enterprise value, potentially driven in part by a loyal and emerging base of over 175,000 clients worldwid, Cryo-Cell’s expansive IP portfolio and an independently funded R&D pipeline, in addition to the company’s progressive global leadership in stem cell innovation.”

Cryo-Cell is one of the world’s largest cord blood banks, having collected over 175,000 cord blood specimens from newborns around the world since its founding in 1992. Headquartered in Florida, Cryo-Cell specializes in both the processing and cryogenic storage of adult stem cells from umbilical cord blood. Given the fact that prospective clients have increased 94% since last year, it would seem as though an increasing number of people are realizing the benefits of umbilical cord blood banking.

At his home on the New Jersey shore, Higgins was suffering from age-related arthritis. A 9-year-old Golden Retriever, he then underwent a veterinary procedure at the Toms River Animal Hospital in which his own adult canine stem cells were used as his therapy. Now, Higgins is once again pain-free and back to his regular self.

According to veterinarian Dr. Michele Reimer, “In animals, it’s definitely an up-and-coming field and it’s going to open up a lot of treatment approaches for us. It opens another avenue of treatment for the dog. If we can help a dog not need medications long-term, that’s a huge benefit.”

The stem cells were harvested from the adipose (fat) tissue of the dog’s belly on Monday, shipped to the biotech company Vet-Stem in San Diego, and returned to the clinic in New Jersey by Wednesday, at which time the cells were injected directly into the dog’s arthritic joints.

According to Julie Ryan Johnson, vice president of sales and marketing for Vet-Stem, “The procedure has been shown to help with the range of motion, helps get muscle structure back, helps the dog feel better and improves their quality of life, and they often interact with the family more. It’s a very interesting way to use stem cells because the stem cells actually come from the animal’s own fat, so it’s not controversial.”

As previously reported a number of times on this website, the company Vet-Stem continues to see consistently high success rates in both canine and equine clinical trials, with an 80% efficacy rate and a 100% safety rate in the animals that are treated with Vet-Stem’s autologous adult stem cell procedure. In other words, 80% of the animals treated are found to experience improvement in their condition with a reduction and often a full elimination of the need for medication, while adverse side effects have not been reported in any of the treated animals.

Vet-Stem uses exclusively adult stem cells, derived from each animal’s own tissue. Since the cells are autologous (in which the donor and recipient are the same animal), there is no risk of immune rejection. More specifically, the stem cells that are harvested in Vet-Stem’s procedure are mesenchymal stem cells, which are highly potent adult stem cells that are also found in bone marrow and umbilical cord blood. Numerous scientific and clinical studies have been published in the peer-reviewed medical literature detailing the regenerative properties of mesenchymal stem cells. No embryonic stem cells are ever used in Vet-Stem’s therapies, since embryonic stem cells are highly problematic in the laboratory, whether they are of human or non-human origin. Among other problems, the risk of teratoma (tumor) formation disqualifies embryonic stem cells for use as a clinical therapy, even in animals. Adult stem cells, however, do not pose such risks and are therefore rapidly accumulating a consistent history of successful clinical treatments in veterinary, as well as in human, medicine.