(HealthDay News) The majority of embryonic stem cell research is being conducted on lines that have been established years ago from frozen in vitro fertilization embryos. Many times the ethnic origin of these cells is not known, or when it is, specific issues as to country of origin versus actual ethnicity are not clear.
Scientists at the Scripps Research Institute in La Jolla, California have reported what they believe to be a potential solution to this puzzle. The team, lead by Dr. Jeanne Loring, published a paper in the January 2010 edition of the journal Nature Methods in which they reveal a molecular technique that could be useful for answering this question.

"Ethnic origin is a critical piece of information that should come with every cell line," said Dr. Loring. "Everyone who works with stem cells should be doing this kind of analysis."

Dr. Loring was referring to numerous situations in which different ethnicities have different biological responses to drugs or medical treatments. Although in the majority of cases these differences are subtle, situations such as metabolism of specific drugs or organ rejection can have terrible consequences if ethnicity is not taken into consideration. In the study, Dr. Loring’s team analyzed a variety of human embryonic stem cell lines that are being used in laboratory research internationally. Of these cell lines, the majority originated from donors of Caucasian and East Asian descend, with no representation from Africa.

In order to address this problem, brand new stem cells were generated using the inducible pluripotent stem cell (iPS) method from a donor of West African Yoruba origin. This cell line was the first pluripotent cell line to have the genetic make-up of a person from this ethnic group. The iPS technology essentially allows for the generation of cells that resemble both functionally, and molecularly embryonic stem cells without the need for using fertilized eggs. Scientists have previously reported that introduction of certain genes into skin cells, or other types of adult cells, can be used to "de-differentiate" adult cells into a phenotype that resembles embryonic stem cells. By being able to take adult cells and generated cells that resemble embryonic stem cells, scientists such as Dr. Loring have made pluripotent stem cell lines not only from humans of different ethnicities, but also individuals with various diseases, as well as animals at risk of extinction.

"Knowing that a big push in the future is using these lines in the clinic and in drug development, there’s a need to have an ethnically diverse population of cells," added Louise Laurent, M.D., Ph.D., assistant professor at the University of California, San Diego (UCSD) and research associate at Scripps Research, who is first author of the paper with Caroline Nievergelt, Ph.D., also an assistant professor at UCSD.

The current research was based on a previously described molecular biology technology in which specific gene signatures are correlated with ancestry of individuals. On such project, the International HapMap Project, was published in the journal Nature in 2003. This effort linked single-letter alterations in the genetic code — known as single nucleotide polymorphisms, or SNPs — with people of known ethnic origins. This data provided a way to identify the ethnic heritage of a donor of any cell.
"There’s not a lot of value in making a new pluripotent stem cell line now unless it has something new to offer," said Loring. "I think that increasing ethnicity and genetic diversity is an important reason for generating new lines."

"Essentially this publication represents a shift in our thinking about stem cells. Initially the major issue in stem cell research has been how to generate different tissues, now scientists are beginning to take it for granted that tissue generation is occurring and the next issues of transplantation, matching, and scale-up are being considered".

Classically Big Pharma has been focused on development small molecule drugs that can be readily made en masse, and whose chemistry is well understood. Biologics such as antibodies have also been gaining popularity, albeit at a slower rate. Stem cells are more difficult than biologics in terms of manufacturing, however, despite this, there has been some increasing interest by Big Pharma in this area in the last couple years. For example, in June 24th, 2008 Pfizer provided Series A funding for EyeCyte, a San Diego company dedicated to generating cell based treatments for diabetic retinopathy. A mega-deal between Osiris Therapeutics and Genzyme worth over a billion dollars was signed on Nov 4, 2008 for the rest of world rights for the mesenchymal stem cell products Prochymal and Chondrogen.

On August 7, 2009 Opexa and Novartis signed a $50 million deal involving a $4 million upfront payment for a pre-clinical stem cell technology. More recently, Pfizer signed a deal worth $111 million with Athersys involving development of the MultiStem product in the area of inflammatory bowel disease.

"Pfizer is committed to the development of new medicines that have the potential to fundamentally improve the quality of clinical care in areas of need. We are delighted to work with Athersys to develop MultiStem for inflammatory bowel disease," said Dr. Ruth McKernan, Head of Pfizer Regenerative Medicine. "This is an innovative new area and our collaboration with Athersys represents a cornerstone of Pfizer’s stem cell and regenerative medicine strategy."

Athersys is a clinical stage biopharmaceutical company that is developing both stem cell and non-stem cell based drugs. Its Regenerative medicine pipeline includes the use of MultiStem for acute myocardial infarction, bone marrow transplant support, and ischemic stroke. Its small molecule drug pipeline contains novel pharmaceuticals to treat indications such as obesity, as well as certain conditions that affect cognition, attention and wakefulness.

The MultiStem product is a mesenchymal-like stem cell that is capable of becoming numerous types of tissues including heart, brain, muscle, and blood vessels. As found for mesenchymal stem cells derived from other sources, the MultiStem product does not require matching with the recipient. This allows for cells to be used as "universal donor" or a "one size fits all" approach.

"We have been systematically evaluating potential partnering opportunities in multiple areas, and we believe that Pfizer represents the ideal partner for this program," said Dr. Gil Van Bokkelen, Chairman and Chief Executive Officer at Athersys. "Their longstanding global leadership in development and commercialization of new medicines, focus on best-in-class therapies, and their growing commitment to regenerative medicine provide a great foundation for working together."

One of the mysteries of stem cell biology is how these cells can on the one hand make copies of themselves (called self-renewal), and depending on the needs of the body, become different cells, a process called differentiation. It is known that the process of differentiation is dependent on various chemical signals. For example, if one climbs on a mountain, the lack of oxygen stimulates cells within the kidney to make the hormone erythropoietin which increases the number of bone marrow stem cells that differentiate into red blood cells. While some of the signaling proteins are known, the effector proteins inside the stem cell that dictate its activity are still not very well understood.

In two recent back-to-back publications in the Dec 17 issue of Nature, some progress was reported in the understanding of stem-cell growth and differentiation. It was demonstrated that there exist three critical proteins which first stimulate stem cells to proliferate. Then, as the cells differentiate into their final cell type, these proteins switch function and arrest the cells from dividing any more. Because of their central role, the proteins could offer a safe and novel therapeutic target in many cancers. The proteins that arrest the multiplication of the cell may be considered as "tumor suppressor" proteins.

The published study, which was led by researchers at the Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, demonstrated that three proteins, called E2f1, E2f2 and E2f3, play a fundamental role in the differentiation steps that stem cells undergo as they lose their self-renewal activity. One of the interesting findings of the studies was the importance of the Rb tumor suppressor protein in blocking self-renewal of stem cells that are differentiating.

"We show that these E2fs are gene activators in stem cells but then switch to gene repressors when stem cells begin differentiating," says Gustavo Leone, associate professor of molecular virology, immunology and medical genetics at Ohio State’s James Cancer Hospital and Solove Research Institute. Leone headed the first of the two Nature studies and is a co-author on the second.

"This is a very important step in the process of differentiation," Leone says. "As organs form during development, there comes a time when their growth must stop because an organ needs only a certain number of cells and no more. The switch by these proteins from activators to repressors is essential for that to happen. Before this, there was no suspicion that these regulatory proteins had any role in differentiated cells," says Leone. "It was thought they were important only in proliferating cells like stem cells. But that’s not true."

Another interesting finding was that the E2f1, E2f2 and E2f3 proteins, while being inhibited in differentiated cells, can actually be re-activated in the presence of mutated tumor suppressor genes and lead to unrestricted cell growth. This provides another method of generating cancer cells in vitro for testing.

One of the biggest challenges to the treatment of cancer is overcoming the ability of cancer cells to become resistant to drugs or radiation. The problem of resistance is particularly relevant in brain cancers called gliomas. Research published in the Journal Stem Cells reports one method of overcoming this problem.

Scientists at Duke University and the Cleveland Clinic claim to have identified molecules associated with the ability of certain cells within a glioma, called tumor stem cells, to resist radiation. Specifically, they have identified a protein called "Notch", which is normally involved in embryonic development, that seems to be selectively found in resistant cells. Using genetic engineering methods they have made cells that were previously sensitive to radiation to become resistant by inducing expression of Notch.

Dr. Jialiang Wang of Duke University, who is the lead author of the study. said the finding marked the first report that Notch signaling in tumor tissue is related to the failure of radiation treatments.

"This makes the Notch pathway an attractive drug target," Wang said. "The right drug may be able to stop the real bad guys, the glioma stem cells."
The authors have also demonstrated that by inhibiting activity of the Notch protein, through administration of chemicals known as gamma-secretase inhibitors, can result in making resistant cells sensitive to radiation.

These findings are interesting in light of another very recent publication (Zhen et al. Arsenic trioxide-mediated Notch pathway inhibition depletes the cancer stem-like cell population in gliomas. Cancer Lett. 2009 Dec 3) in which the anti-leukemic drug Arsenic Trioxide was also demonstrated to alter glioma stem cells through manipulation of the Notch pathway. Notch has been found in numerous other types of tumor stem cells such as breast, colon, lung, and prostate cancer. The expression of a protein in cancer cells that is supposed to be only expressed during embryonic development supports the theory that during formation of cancer, mature cells tend to revert to an embryonic-like phenotype. This is also exemplified by the fact that adding cancer genes (oncogenes) in combination with some specific proteins can take an adult skin cell and transform it into a cell that resembles the embryonic stem cell, called an "iPS" cell. This is described in the following video: