Baby steps toepigenetics
Most of the research being conducted now is gaining groundin understanding what epigenetics is. Understanding how to influence changes atthis level is still a science that is in its infancy.The exploration of stem cell epigenetics is expected toyield two different outcomes. The problem is that manipulating cells at this levelmay help, but it may hurt, too.Purposely making epigenetic changes at the cell line levelmay 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 expertssay that combining this field with the knowledge of the human genome may allowmanipulation in the future to hunt down and remove biomarkers.So, now that we understand that plastic water bottles arebad for our progeny, and us can we make the leap to find out what's good forour billions of cells?
Biomarkers hold thekey
What this gives us is a big clue—a biomarker for a certaindisease or condition. Biomarkers, of course, provide a valuable part of thediagnostic puzzle.
Baylin is equally exuberant about the possibilities withepigenetic changes. He says manipulating cells at this level could hold promisein just about any disease one could imagine.
"As adults, renewal of our cells is all under epigeneticcontrol," he says. "While epigenetics is a hallmark of how embryos develop,stem cells enable cells to make switches to become the cells they are destinedto be."
Stem cells, then, can provide important healing propertiesat 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 withDebbie Toscano at Frost & Sullivan, a business consulting firm. She listedseveral 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 oneof the first profitable stem cell companies," Toscano says.
The company recently announced that its scientists havecreated a new protein-based stem cell technology through its subsidiary,Lifeline Cell Technology (LCT).The technology modifies human stem cells by using engineeredproteins, called "transducible transcription factors," or TTFs. TTFs aredesigned to pass into stem cells and direct the stem cells to change intospecific cell types that can be both therapeutically useful and used asrevenue-generating research products.
In contrast to more traditional cell therapy methods, thistechnology does not require the use of viruses or chemicals, and has thepotential to produce safe therapeutic cells from stem cells. In addition, theTTF proteins are naturally eliminated by the cells when they are no longerrequired. Once perfected, the company intends to sell revenue-generatingresearch products it will subsequently create through LCT to the academic,biotechnology and pharmaceutical markets for cellular proteins, including thequickly growing markets for the study of stem-cell biology and drug testing.
ISCO is focused on the therapeutic applications of humanparthenogenetic stem cells (hpSCs) and the development and commercialization ofcell-based research and cosmetic products. These types of stem cells areslightly different than MSCs, iPSCs and of course, human embryonic stem cells(hESCs). ISCO's core technology, parthenogenesis, results in the creation ofpluripotent human stem cells from unfertilized human eggs, thereby avoiding theethical 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 forhundreds of millions of individuals of differing genders, ages and racialbackground with minimal immune rejection after transplantation. hpSCs offer thepotential to create the first true stem cell bank, UniStemCell.
ISCO alsoproduces and markets specialized cells and growth media for therapeuticresearch worldwide through its subsidiary, LCT, and stem cell-based skin careproducts through another subsidiary, Lifeline Skin Care.
Toscano also mentions Aastrom Biosciences for chronic limbischemia, Aldagen for ischemic stroke, AlloCure Inc. for kidney injury, StemCells Inc. for spinal cord injuries and Osiris Therapeutics forgraft-versus-host disease (GvHD), Crohn's disease and acute radiation syndrome.
We know that the history of stem cells can be traced back toJapan and Canada. In fact, as reported last month, Canadian scientists layclaim to the discovery of stem cells—the Toronto-based duo of Ernest ArmstrongMcCulloch and James Till famously illustrated the presence of self-renewingcells in mouse bone marrow in the 1960s. Japanese researcher Shinya Yamanakamade an important advance in the field just seven years ago when hesuccessfully reprogrammed human adult cells to function like pluripotentembryonic stem cells.
The two countries made headlines again in March, whenresearchers from both companies forged an international partnership agreementto fund joint research projects on the epigenetics of stem cells. Thecollaborative agreement brings together the Canadian Institutes of HealthResearch (CIHR), a health research investment agency of the Canadiangovernment, and the Japan Science and Technology Agency (JST), an integratedorganization for promoting innovation-oriented science and technology in Japanto advance national welfare and prosperity.
"The goal of this joint research program is to advance novelbiological knowledge in the epigenetics of stem cells," said Dr. MichiharuNakamura, president of the JST, in a statement. "It is also expected that thecollaborative research among Japanese and Canadian scientists will contributeto develop innovative treatment methodologies for clinical medicine."
Dr. Anthony Phillips, scientific director of the CIHR'sInstitute of Neurosciences, Mental Health and Addiction, says the explorationof stem cell epigenetics is expected to yield two different outcomes.
"One is cautionary—we want to know whether epigeneticchanges will assure a practitioner that a cell line won't have deeper problemswith time," he explains. "On the more applied side, epigenetics is moving tothe point where potentially over the next five to 10 years, it may be possibleto impose an epigenetic set of characteristics on the genome, or see if thereare negative marks that you can remove. This is something that could bias anapplication toward a better outcome, or prevent a negative outcome fromoccurring."
In addition, "we're seeing more on the epigenetics of cancercells now, and scientists are providing fairly accurate biomarkers of certainproblems," Phillips notes. "This could be quite important from a diagnosticperspective. Another application might be in terms of environmental toxins andhow they might change epigenetic factors."
Canada is apparently leading the research pack again, asOsiris shook the stem cell community in May when it announced that it hadgained approval for Prochymal, a stem cell therapy, there. The Maryland-basedcompany became the first U.S. company authorized to sell a stem cell-basedtreatment—albeit in its neighbor to the north.
If the medical community wants to exploit the potential ofstem cells to make changes to established human cells that have succumbed todisease states, then the Osiris news is truly a milestone.
Case study: Stem cellattack is an unfortunate result of a 'cure' for cancer
Imagine that you have a child who is being treated forleukemia. Instead of being helped, the therapy which is intended to destroy thedanger lurking in his bone marrow instead changes into something entirelydifferent and frightening—and mostly fatal.
GvHD is an awful way to die. It's awful for parents toobserve as well. GvHD is a complication of bone marrow transplantation thatkills up to 80 percent of children affected, many within weeks. It is theleading cause of transplant-related mortality. GvHD victims can suffer fromsevere blistering of the skin, intestinal hemorrhages and liver failure.
Thefirst-line therapy is usually steroids, but that works at best in only half ofthe cases where it's tried.Through the discovery and testing of Prochymal, stem cellsas treatment have taken a huge leap forward—no matter the type of stem cellbeing considered or its mechanism of action.
Prochymal, a preparation of MSCs, will be used to treatchildren suffering from GvHD, a potentially deadly complication of bone marrowtransplantation. Patients with this condition are sometimes treated withsteroids or other drugs to suppress their immune systems' attack, but thisisn't always effective, and patients may die.
Canadian regulators have approved Prochymal for childrenwhose condition is not controlled by steroids. In clinical trials, about 60percent of such children responded meaningfully to the drug.
Prochymal has not, of course, been without failures. Thedrug failed late-stage clinical trials in 2009.
Dr. Joanne Kurtzberg is another giant in the field of stemcells. She's currently the head of pediatric transplantation at DukeUniversity, and is the lead investigator in the Prochymal trials. Her expertisespans 30 years, and falls mainly in the field of hESCs. It's remarkable thatshe's lent her reputation to the development of this drug, especially since itfailed in original trials and had been abandoned.
"This therapy, Prochymal, gives real hope that GvHD can beless deadly," she says. "It's been tested extensively, and is an off-the-shelfproduct that has shown remarkable results."
The ebullient Dr. C. Randal Mills, president and CEO ofOsiris, describes a case study in which a young patient, who quickly developedGvHD as a result of a bone-marrow transplant, responded so quickly to Prochymalthat 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 thisheartbreaking condition, and hope for approval to sell this productcommercially this year."
Another important fact about Prochymal is that it comes fromthe bone marrow of healthy donors ages 18 to 30. It's easy to administer—itcomes as an off-the-shelf stem-cell product that is stored frozen at thepoint-of-care and infused through a simple I.V. line without the need to typeor immunosuppress the recipient. Remarkably, a single bone marrow donation cangive rise to approximately 10,000 doses of Prochymal, each with a 42-monthshelf life.
In Canada, Prochymal is now authorized for the management ofacute GvHD in children who fail to respond to steroids. The approval was basedon the results from clinical studies evaluating Prochymal in patients withsevere refractory acute GvHD. Prochymal demonstrated a clinically meaningfulresponse at 28 days post-initiation of therapy in 61 to 64 percent of patientstreated. Treatment with Prochymal resulted in a statistically significantimprovement in survival when compared to a historical control population ofpediatric patients with refractory GvHD. The survival benefit was mostpronounced in patients with the most severe forms of GvHD.
"Refractory GvHD is not just deadly to the patients itafflicts, but is devastating for the family, friends and caregivers who watchhelplessly as the disease progresses," says Dr. Joanne Kurtzberg, head of thePediatric Bone Marrow Transplant program at Duke University and lead investigatorfor Prochymal. "I have personally seen Prochymal reverse the debilitatingeffects of severe GvHD in many of my patients, and now, after nearly twodecades of research, the data demonstrating consistently high response rates, astrong safety profile and improved survival clearly support the use ofProchymal in the management of refractory GvHD."
As we went to press, Osiris won a second approval forProchymal in New Zealand. The company plans to seek U.S. Food and DrugAdministration approval for Prochymal later this year. Osiris is also trying todevelop Prochymal as a treatment for Crohn's disease, diabetes, heart attacksand other illnesses.
Across the pond … again
In June, GE Healthcare, the healthcare business of GE andbehemoth Chinese genomics concern BGI, announced a pioneering, multiyearresearch collaboration in stem-cell science to advance the global use of stemcell-derived assays for use in drug discovery and toxicity testing.
What'snovel is that this partnership will dive further by exploring the underlyinggenetic variation between ethnically diverse human stem cell lines.Initially, the partnership will involve two projects. BGI isperforming genome sequencing and epigenetic analysis on cardiomyocytes andhepatocytes supplied by GE Healthcare Life Sciences. The aim is to map out thegenetic variation across an ethnically diverse range of stem cell lines, and toexamine the changes that occur during differentiation into specific cell typesin order to increase the understanding of cell models used in drug developmentresearch.
GE Healthcare is providing BGI with high-tech research toolsfor high-content cellular imaging analysis, as well as the necessary training toinvestigate gene function for a library of previously sequenced cell types byoverexpressing or blocking the activity of single genes and observing theeffect in selected populations of cells.This level of detail, backed by a healthcare giant, givesweight to the promise of epigenetics and provides technical support to themyriad back-of-the-house functions that need to take place to make this area ofresearch leap from the dish to the clinic. The key will be making availablemore biologically relevant and predictive cell models.
The nice twist with thispartnership is that individual variations in the basic cellular composition ofhumans based on ethnicity will now enter the mix. Genetic variation analysis offunctional cells derived from hESCs will hopefully provide a promising cellmodel resource for drug development and cell therapy.
Baylin, though, may address the promise of epigenetics thebest.
"Theoretically, stem-cell therapies can have uses throughoutthe body," he says. "Epigenetics goes right to the heart of how things go wrongin cancer. This area has really come to the fore in cancer research."
In many cancers, he says, subgroups of cancer cells keeptumors growing. These can have epigenetic abnormalities that can make cellsrenew, or conversely, fail to develop properly.
"We need to find these epigenetic changes as markers anddetermine how to reverse those changes," he says. "Ideally, we'll use drugsthat are available, and help cells grow normally, or at least grow the way theywere 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 orsmall."
Most hopefully, though, Baylin feels the field may be readyto make the clinical leap soon. He expects that some of his own work in lungcancer may have the patient numbers within the next year or two to make thatleap, calling the work "extremely promising.""If it holds, it might come into clinical management in thenext couple years, along with some other newer agents," he concludes.