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Epigenetics: Half of the picture (PART 2)
Baby steps to epigenetics
Most of the research being conducted now is gaining ground in understanding what epigenetics is. Understanding how to influence changes at this level is still a science that is in its infancy. The exploration of stem cell epigenetics is expected to yield two different outcomes. The problem is that manipulating cells at this level may help, but it may hurt, too. Purposely making epigenetic changes at the cell line level may manifest in a harmful way over time, as Skinner's research suggests.
Although this arm of science is so new, it is imbued with hope. Most experts say that combining this field with the knowledge of the human genome may allow manipulation in the future to hunt down and remove biomarkers. So, now that we understand that plastic water bottles are bad for our progeny, and us can we make the leap to find out what's good for our billions of cells?
Biomarkers hold the key
What this gives us is a big clue—a biomarker for a certain disease or condition. Biomarkers, of course, provide a valuable part of the diagnostic puzzle.
Baylin is equally exuberant about the possibilities with epigenetic changes. He says manipulating cells at this level could hold promise in just about any disease one could imagine.
"As adults, renewal of our cells is all under epigenetic control," he says. "While epigenetics is a hallmark of how embryos develop, stem cells enable cells to make switches to become the cells they are destined to be."
Stem cells, then, can provide important healing properties at the very basic levels of flaws in human composition.
Players in the field
So who are the ones to watch in this space? We spoke with Debbie Toscano at Frost & Sullivan, a business consulting firm. She listed several companies she thinks are the ones to watch in stem cell research. One company she mentioned, which was in the news recently, is International Stem Cell Corp. (ISCO): "It's considered by analysts to be one of the first profitable stem cell companies," Toscano says.
The company recently announced that its scientists have created a new protein-based stem cell technology through its subsidiary, Lifeline Cell Technology (LCT). The technology modifies human stem cells by using engineered proteins, called "transducible transcription factors," or TTFs. TTFs are designed to pass into stem cells and direct the stem cells to change into specific cell types that can be both therapeutically useful and used as revenue-generating research products.
In contrast to more traditional cell therapy methods, this technology does not require the use of viruses or chemicals, and has the potential to produce safe therapeutic cells from stem cells. In addition, the TTF proteins are naturally eliminated by the cells when they are no longer required. Once perfected, the company intends to sell revenue-generating research products it will subsequently create through LCT to the academic, biotechnology and pharmaceutical markets for cellular proteins, including the quickly growing markets for the study of stem-cell biology and drug testing.
ISCO is focused on the therapeutic applications of human parthenogenetic stem cells (hpSCs) and the development and commercialization of cell-based research and cosmetic products. These types of stem cells are slightly different than MSCs, iPSCs and of course, human embryonic stem cells (hESCs). ISCO's core technology, parthenogenesis, results in the creation of pluripotent human stem cells from unfertilized human eggs, thereby avoiding the ethical issues associated with the use or destruction of viable human embryos. ISCO scientists have created the first parthenogenic, homozygous stem cell line that can be a source of therapeutic cells for hundreds of millions of individuals of differing genders, ages and racial background with minimal immune rejection after transplantation. hpSCs offer the potential to create the first true stem cell bank, UniStemCell.
ISCO also produces and markets specialized cells and growth media for therapeutic research worldwide through its subsidiary, LCT, and stem cell-based skin care products through another subsidiary, Lifeline Skin Care.
Toscano also mentions Aastrom Biosciences for chronic limb ischemia, Aldagen for ischemic stroke, AlloCure Inc. for kidney injury, Stem Cells Inc. for spinal cord injuries and Osiris Therapeutics for graft-versus-host disease (GvHD), Crohn's disease and acute radiation syndrome.
We know that the history of stem cells can be traced back to Japan and Canada. In fact, as reported last month, Canadian scientists lay claim to the discovery of stem cells—the Toronto-based duo of Ernest Armstrong McCulloch and James Till famously illustrated the presence of self-renewing cells in mouse bone marrow in the 1960s. Japanese researcher Shinya Yamanaka made an important advance in the field just seven years ago when he successfully reprogrammed human adult cells to function like pluripotent embryonic stem cells.
The two countries made headlines again in March, when researchers from both companies forged an international partnership agreement to fund joint research projects on the epigenetics of stem cells. The collaborative agreement brings together the Canadian Institutes of Health Research (CIHR), a health research investment agency of the Canadian government, and the Japan Science and Technology Agency (JST), an integrated organization for promoting innovation-oriented science and technology in Japan to advance national welfare and prosperity.
"The goal of this joint research program is to advance novel biological knowledge in the epigenetics of stem cells," said Dr. Michiharu Nakamura, president of the JST, in a statement. "It is also expected that the collaborative research among Japanese and Canadian scientists will contribute to develop innovative treatment methodologies for clinical medicine."
Dr. Anthony Phillips, scientific director of the CIHR's Institute of Neurosciences, Mental Health and Addiction, says the exploration of stem cell epigenetics is expected to yield two different outcomes.
"One is cautionary—we want to know whether epigenetic changes will assure a practitioner that a cell line won't have deeper problems with time," he explains. "On the more applied side, epigenetics is moving to the point where potentially over the next five to 10 years, it may be possible to impose an epigenetic set of characteristics on the genome, or see if there are negative marks that you can remove. This is something that could bias an application toward a better outcome, or prevent a negative outcome from occurring."
In addition, "we're seeing more on the epigenetics of cancer cells now, and scientists are providing fairly accurate biomarkers of certain problems," Phillips notes. "This could be quite important from a diagnostic perspective. Another application might be in terms of environmental toxins and how they might change epigenetic factors."
Canada is apparently leading the research pack again, as Osiris shook the stem cell community in May when it announced that it had gained approval for Prochymal, a stem cell therapy, there. The Maryland-based company became the first U.S. company authorized to sell a stem cell-based treatment—albeit in its neighbor to the north.
If the medical community wants to exploit the potential of stem cells to make changes to established human cells that have succumbed to disease states, then the Osiris news is truly a milestone.
Case study: Stem cell attack is an unfortunate result of a 'cure' for cancer
Imagine that you have a child who is being treated for leukemia. Instead of being helped, the therapy which is intended to destroy the danger lurking in his bone marrow instead changes into something entirely different and frightening—and mostly fatal.
GvHD is an awful way to die. It's awful for parents to observe as well. GvHD is a complication of bone marrow transplantation that kills up to 80 percent of children affected, many within weeks. It is the leading cause of transplant-related mortality. GvHD victims can suffer from severe blistering of the skin, intestinal hemorrhages and liver failure.
The first-line therapy is usually steroids, but that works at best in only half of the cases where it's tried. Through the discovery and testing of Prochymal, stem cells as treatment have taken a huge leap forward—no matter the type of stem cell being considered or its mechanism of action.
Prochymal, a preparation of MSCs, will be used to treat children suffering from GvHD, a potentially deadly complication of bone marrow transplantation. Patients with this condition are sometimes treated with steroids or other drugs to suppress their immune systems' attack, but this isn't always effective, and patients may die.
Canadian regulators have approved Prochymal for children whose condition is not controlled by steroids. In clinical trials, about 60 percent of such children responded meaningfully to the drug.
Prochymal has not, of course, been without failures. The drug failed late-stage clinical trials in 2009.
Dr. Joanne Kurtzberg is another giant in the field of stem cells. She's currently the head of pediatric transplantation at Duke University, and is the lead investigator in the Prochymal trials. Her expertise spans 30 years, and falls mainly in the field of hESCs. It's remarkable that she's lent her reputation to the development of this drug, especially since it failed in original trials and had been abandoned.
"This therapy, Prochymal, gives real hope that GvHD can be less deadly," she says. "It's been tested extensively, and is an off-the-shelf product that has shown remarkable results."
The ebullient Dr. C. Randal Mills, president and CEO of Osiris, describes a case study in which a young patient, who quickly developed GvHD as a result of a bone-marrow transplant, responded so quickly to Prochymal that he went from gravely ill to leaving the hospital within a few days.
"It was gratifying to learn of this young man's success," says Mills. "We are glad that we were able to make progress in treating this heartbreaking condition, and hope for approval to sell this product commercially this year."
Another important fact about Prochymal is that it comes from the bone marrow of healthy donors ages 18 to 30. It's easy to administer—it comes as an off-the-shelf stem-cell product that is stored frozen at the point-of-care and infused through a simple I.V. line without the need to type or immunosuppress the recipient. Remarkably, a single bone marrow donation can give rise to approximately 10,000 doses of Prochymal, each with a 42-month shelf life.
In Canada, Prochymal is now authorized for the management of acute GvHD in children who fail to respond to steroids. The approval was based on the results from clinical studies evaluating Prochymal in patients with severe refractory acute GvHD. Prochymal demonstrated a clinically meaningful response at 28 days post-initiation of therapy in 61 to 64 percent of patients treated. Treatment with Prochymal resulted in a statistically significant improvement in survival when compared to a historical control population of pediatric patients with refractory GvHD. The survival benefit was most pronounced in patients with the most severe forms of GvHD.
"Refractory GvHD is not just deadly to the patients it afflicts, but is devastating for the family, friends and caregivers who watch helplessly as the disease progresses," says Dr. Joanne Kurtzberg, head of the Pediatric Bone Marrow Transplant program at Duke University and lead investigator for Prochymal. "I have personally seen Prochymal reverse the debilitating effects of severe GvHD in many of my patients, and now, after nearly two decades of research, the data demonstrating consistently high response rates, a strong safety profile and improved survival clearly support the use of Prochymal in the management of refractory GvHD."
As we went to press, Osiris won a second approval for Prochymal in New Zealand. The company plans to seek U.S. Food and Drug Administration approval for Prochymal later this year. Osiris is also trying to develop Prochymal as a treatment for Crohn's disease, diabetes, heart attacks and other illnesses.
Across the pond … again
In June, GE Healthcare, the healthcare business of GE and behemoth Chinese genomics concern BGI, announced a pioneering, multiyear research collaboration in stem-cell science to advance the global use of stem cell-derived assays for use in drug discovery and toxicity testing.
What's novel is that this partnership will dive further by exploring the underlying genetic variation between ethnically diverse human stem cell lines. Initially, the partnership will involve two projects. BGI is performing genome sequencing and epigenetic analysis on cardiomyocytes and hepatocytes supplied by GE Healthcare Life Sciences. The aim is to map out the genetic variation across an ethnically diverse range of stem cell lines, and to examine the changes that occur during differentiation into specific cell types in order to increase the understanding of cell models used in drug development research.
GE Healthcare is providing BGI with high-tech research tools for high-content cellular imaging analysis, as well as the necessary training to investigate gene function for a library of previously sequenced cell types by overexpressing or blocking the activity of single genes and observing the effect in selected populations of cells. This level of detail, backed by a healthcare giant, gives weight to the promise of epigenetics and provides technical support to the myriad back-of-the-house functions that need to take place to make this area of research leap from the dish to the clinic. The key will be making available more biologically relevant and predictive cell models.
The nice twist with this partnership is that individual variations in the basic cellular composition of humans based on ethnicity will now enter the mix. Genetic variation analysis of functional cells derived from hESCs will hopefully provide a promising cell model resource for drug development and cell therapy.
Baylin, though, may address the promise of epigenetics the best.
"Theoretically, stem-cell therapies can have uses throughout the body," he says. "Epigenetics goes right to the heart of how things go wrong in cancer. This area has really come to the fore in cancer research."
In many cancers, he says, subgroups of cancer cells keep tumors growing. These can have epigenetic abnormalities that can make cells renew, or conversely, fail to develop properly.
"We need to find these epigenetic changes as markers and determine how to reverse those changes," he says. "Ideally, we'll use drugs that are available, and help cells grow normally, or at least grow the way they were intended to. We're getting traction in the clinic now with older drugs. Every major pharma company is involved in this field in some way, large or small."
Most hopefully, though, Baylin feels the field may be ready to make the clinical leap soon. He expects that some of his own work in lung cancer may have the patient numbers within the next year or two to make that leap, calling the work "extremely promising." "If it holds, it might come into clinical management in the next couple years, along with some other newer agents," he concludes.