The promise, the pitfalls and a paradigm shift, PART 1

The complex history of stem cell research yields hope for improved human health, unresolved concerns

Amy Swinderman
To the powerful Michael J. Fox Foundation for Parkinson'sResearch, stem cell research gives scientists a "pathway" to fighting the devastatingeffects of—or even curing—Parkinson's disease. To others opposed to one form ofstem cell research—the approach that uses human embryos—it "devalues andviolates human life," as Pope John Paul II once said.
 
 
How these parties arrived at these diverging conclusionsabout stem cell research is the product of scientific discoveries meeting withchanging public discourse, but the one constant in the evolution of thisburgeoning area of research is the promise it holds for human health. But althoughbillions of dollars have been spent in the quest to realize this promise,thousands of patents have been issued on stem-cell related technologies andhundreds of companies have been impacted in some way by stem cell research, itis still a scientific field with many hurdles to overcome and divisive concernsyet to be addressed.
 
In this, our first installment of a three-part series onstem cell research, we explore the history and evolution of the field, whatprogress has been made and finally, what challenges lay ahead.
 
 
Planting the idea
 
 
According to many historic accounts, the term "stem cell"dates as far back as 1908, when a Russian-American histologist named AlexanderMaksimov found that certain cells could generate blood cells. Legend holds thatMaksimov—renowned for his experimental work confirming the Unitarian theory ofhematopoiesis—poetically coined the term after noting that the stem of a treegives rise to a variety of branches.
 
 
It wasn't until almost a half a century later that thistheory saw significant progress. In fact, according to Dr. David T. Scadden,co-chair of the Harvard Stem Cell Institute, it wasn't until World War II andthe introduction of nuclear weapons that scientists picked up where Maksimovand his colleagues left off.
 
 
"There was a tremendous amount of concern raised,particularly in the United States and Canada, about understanding the nature ofradiation injury and how to protect people from it or help them overcome it,"Scadden says.
 
 
One of the most areas most affected by radiation was blood,says Scadden, but this theory was not experimentally defined until the early1960s, when University of Toronto researchers Ernest Armstrong McCulloch and JamesTill injected bone marrow cells into irradiated mice, and proved that visiblenodules observed in the spleens of the mice arose from a single marrow cell.
 
In the next two decades, other researchers discovered thepluripotent tendencies of these cells, or their ability to differentiate intomany different cell types. Then, in 1981, two groups derived embryonic stemcells (ESCs) from mouse embryos: Martin Evans and Matthew Kaufman from theUniversity of Cambridge, and Gail R. Martin from the University of California,San Francisco.
 
 
In 1982, Dr. Curt Civin, then an oncologist and nowassociate dean of research at the University of Maryland School of Medicine,discovered a monoclonal antibody that allowed scientists to identify and purifyblood-forming stem cells. Civin's groundbreaking research has resulted in newtools for diagnosing leukemia and purifying stem cells for research andclinical stem cell transplantation.
 
In 1998, another major breakthrough occurred when thelaboratory of James Thomson at the University of Wisconsin-Madison developed atechnique to isolate and grow human embryonic stem cells (hESCs) in a cellculture.
 
"This is the field that became known as developmentalbiology in the 1990s," says Dr. Deepak Srivastava, director of the GladstoneInstitute of Cardiovascular Disease in San Francisco. "This ushered in the eraof scientists being able, for the first time, to study the precise function ofgenes in an animal model. That burst of information in developmental biologyformed the basis for modern stem cell biology, which involves taking stem cellsand directing them for various regenerative uses."
 
 
In 2006, Japanese researchers in the laboratory of ShinyaYamanaka successfully transformed human fibroblasts into pluripotent stem cellsusing four genes with a retroviral system. Almost simultaneously, Thomson andhis colleagues published similar findings involving different genes using alentiviral system. These cells became known as induced pluripotent stem cells(iPSCs).
 
 
The power and thepotency
 
 
According to the U.S. National Institutes of Health (NIH),these discoveries led to a classical definition of "stem cells," whichincorporates two properties: They must be unspecialized cells capable ofrenewing themselves through cell division, sometimes after long periods ofinactivity, and under certain physiologic or experimental conditions, they canbe induced to become tissue- or organ-specific cells with special functions.
 
 
Within this definition, scientists have a menu of stem celllines from which to select. Adult stem cells (ASCs), also known as somatic stemcells, are extracted from adult tissue without harm to the subject. ASCs havethe ability to differentiate into more than one cell type, but they are oftenrestricted to certain types. Because they are limited in their differentiationcapabilities and can be difficult to harvest, most researchers agree that adultstem cells can only produce a few of the 220 types of cells in the human body.
 
ESCs, derived from the inner cell mass (ICM) of theblastocyst (or early-stage embryo), are pluripotent, or have the ability togenerate all cell types in the body. One of the scientific concerns about ESCsis that they sometimes form tumors.
 
iPSCs are a type of pluripotent stem cell artificiallyderived from a non-pluripotent cell (typically an ASC) by inducing a forced expressionof specific genes. Because they are similar to hESCs, some researchers believethey may have great therapeutic potential without the controversial use ofembryos. However, their full relation to natural pluripotent stem cells is yetto be determined, and since the Yamanaka discovery, some researchers havedemonstrated that they may produce immunogenic responses.
 
Embryonic ethicaldilemma
 
hESCs have been at the center of ethical, moral and social controversyfor the better part of the last two decades. Human embryos reach the blastocyststage four to five days post-fertilization, when they are about the size of agrain of sand and consist of 50 to 150 cells. Because isolating the ICM resultsin the destruction of the fertilized human embryo, significant ethical issueshave been raised.
 
 
Until recently, the principal source of hESCs has beendonated embryos from fertility clinics. If a woman undergoes in-vitro fertilization, and hasfertilized eggs that she does not intend to use, should the donor have theright to consent that these eggs be used for research? Should researchers paywomen to donate their eggs—a process that could involve significant risks?These are questions that have persisted since hESCs were first discovered, and30 years later, society is still working on finding answers—or at leastcompromising consensus—says Dr. Debra J.H. Mathews, assistant director forscience programs at Johns Hopkins University's Berman Institute of Bioethics. 
 
"Science can tell you a lot," says Mathews, who also servesas a senior policy and research analyst for the Presidential Commission for theStudy of Bioethical Issues. "In this particular case, science can tell you thatgiven a willing woman and the right circumstances, a human embryo can become ahuman baby—but science can't say what we owe that entity. That is aphilosophical, existential, religious question. Each individual needs to answerthat question for him or herself, in consultation with his or her family,religion, etc. Science isn't going to help you do that."
 
 
In the years to come, "there needs to be publicconversation, and we need to come to an understanding about what all of thismeans," Mathews says. "We may not come to complete moral agreement, but we canat least come to a political accommodation of how to conduct stem cellresearch."
 
 
Governmentintervention
 
The last three American presidents and their colleagues ingovernment have attempted to do just that. In 1995, President Bill Clintonsigned into law a measure that prohibited the U.S. Department of Health andHuman Services and the NIH from using appropriated funds for the creation ofhuman embryos for research purposes, or for research in which human embryos aredestroyed. Called the Dickey-Wicker Amendment, the legislation was actually arider attached to an unrelated appropriations bill passed by Congress.
 
 
Within the first year of his first term, President George W.Bush announced that federal funds could be awarded for research using hESCs ifthe cell lines were derived prior to Aug. 9, 2001 from an embryo created forreproductive purposes and no longer needed. In addition, informed consent was requiredfor the donation of the embryo, which could not involve financial inducements.
 
 
On June 20, 2007, Bush put teeth into that announcement byissuing Executive Order 13435, "Expanding Approved Stem Cell Lines in EthicallyResponsible Ways." The order provided for the government support of "researchon the isolation, derivation, production and testing of stem cells … derivedwithout creating a human embryo for research purposes or destroying, discardingor subjecting to harm a human embryo or fetus."
 
"What happened in 2001 and during the Bush years was thatonly previously existing cell lines could be used for federally fundedresearch—and this created an issue for people who felt that better cell lineshad to be developed," Scadden recalls. "The federal government is the biggestdriver of research in this area because it is so early in the field, so theseevents shut off a lot of work. One could try to find philanthropic donors, butthat is usually not a resource that is as durable as government grants."
 
On March 9, 2009, President Barack Obama—as one of his firstacts as the nation's newly elected leader—issued Executive Order 13505, "Removing Barriers toResponsible Scientific Research Involving Human Stem Cells," an action intendedto reverse Bush's policy. The order was quickly followed by new NIHguidelines for hESC research and its December 2009 approval of 13 human stemcell lines for research.
 
 
But these events did not have the impact some expected.According to market research firm Frost & Sullivan, NIH funding for stemcell research has traditionally been low. Although the field saw a sharp risein hESC research funding in 2008 and 2009 after Obama's order was handed down,Frost & Sullivan notes that funding for both embryonic and non-embryonicresearch has plateaued at $100 million and $350 million, respectively.
 
 
"Interestingly, despite the economic crisis and governmentcutback in research funds, funding for both non-embryonic and embryonic stemcell lines has risen or remained constant, but has not fallen," says JonathanWitonsky, industry manager of Frost & Sullivan's Drug DiscoveryTechnologies & Clinical Diagnostics division.
Researchers also benefited from the $20 million to $40million in economic stimulus funding provided by the American Recovery andReinvestment Act (ARRA) in 2009 and 2010, the firm adds.
 
 
Despite these actions, Mathews notes that Dickey-Wicker remainsan obstacle for federally funded researchers seeking to create their own stemcell lines, as Congress has renewed it every year without substantive changes.
 
 
"The NIH's guidelines aren't so prescriptive that nothingwill meet the bar," she says. "But so far, Congress hasn't had the politicalwill to get rid of Dickey-Wicker."
 
 
A will and a way
 
 
While legislators may lack the appetite to tackle thisdebate, plaintiffs in lawsuits filed at every court level are seeking the lastword on the use of embryos in stem cell research. Some have failed and some arestill proceeding, but at least one case has researchers squirming, as it itsultimate fate may be decided by the U.S. Supreme Court.
 
 
Sherley, et. al., v.Sebelius, et al., filed in the U.S. District Court for the District ofColumbia, alleges that Obama's executive order violates Dickey-Wicker. Thesuit's lead plaintiffs, adult stem cell researchers Dr. James L. Sherley, abiological engineer at Boston Biomedical Research Institute, and Dr. TheresaDeisher, research and development director at AVM Biotechnology LLC in Seattle,also argue that Obama's order has intensified competition for the limitedgovernment dollars, making it more difficult for them to get funding for theirown work.
 
In August 2010, the court, finding merits in the plaintiff'sfilings, issued a preliminary injunction that brought federal funding forembryo-destructive research to a halt. A month later, the U.S. Court of Appealstemporarily suspended the injunction as the case moved forward. On April 29, thecourt completely reversed the ruling on the grounds that it may impose asubstantial hardship on stem cell researchers who have multi-year projectsalready underway.
 
 
Interestingly, the court also interpreted Dickey-Wicker tomean that hESC research is permissible under its current language—as Congresshas renewed the amendment every year with the knowledge that it funds suchresearch.
 
But given the facts presented in this controversial case, somelegal analysts predict that the last word on Dickey-Wicker may ultimately comein the form of an interpretation by the highest court in the land.
 
"We've had three U.S. presidential interpretations of it,from two Democrats and one Republican," Civin says. "If it goes to the SupremeCourt, I'm a little worried because the Supreme Court has been ideologicallysplit on recent issues. The court could interpret Dickey-Wicker to mean thathESC research is illegal."
 
 
States' rights
 
Where ambiguity exists in this debate on a federal level,some states have drawn a clear line in the sand about which forms of stem cellresearch may be conducted and publicly funded.
 
 
Some states, such as California, not only allow, butencourage stem cell research in all of its forms. In 2002, Gov. Gray Davissigned into law Senate Bill 253, a measure that explicitly allows research onstem cells from fetal and embryonic tissue. Two years later, California votersapproved Proposition 71, creating a $3 billion state taxpayer-funded institutefor stem cell research, the California Institute for Regenerative Medicine.
Other states—many of which are known biotechnologyhubs—showing support for all forms of stem cell research include Connecticut,Florida, Illinois, Maryland, Massachusetts, New Hampshire, New Jersey, NewYork, Pennsylvania, Texas, Washington and Wisconsin.
 
 
However, several states have imposed or are considering additionalrestrictions or even complete bans on hESC research: Arkansas, Indiana,Louisiana, Michigan, North Dakota and South Dakota, to name a few.
 
 
One state, Ohio, took action to put the Bush restrictions inits statutes. Researchers are permitted to conduct hESC research, but they mustnot derive any new cell lines. Thus, Michael Gilkey, acting executive directorof the National Center for Regenerative Medicine (NCRM)—a multi-institutionalcenter composed of investigators from Cleveland's Case Western ReserveUniversity, the Cleveland Clinic and University Hospitals Case MedicalCenter—notes that Ohio researchers never benefited from Obama's more liberal fundingpolicy.
 
 
"Federal and state laws affect stem cell research, andpoliticians need to be careful when enacting laws that restrict and criminallypenalize researchers," Gilkey says. "The cost alone to monitor and prosecutethis would be prohibitive in this economic environment. I think if Ohio followsfederal guidelines presented by the National Institutes of Health and does notmove to restrict specific areas of research, we'd have more economicdevelopment in Ohio. One of our goals is to create a stem cell research andcommercialization hub here in Northeast Ohio. More research means new jobs, newrevenues and new taxes. We just need the right environment to succeed."
 
 
Gilkey says Ohio researchers continue to educate legislatorsseeking to ban hESC research, human cloning and the creation of animal-humanhybrids.
 
 
"You can't create human-animal hybrids like you see inscience fiction—the genome just doesn't work that way," he says. "The problemwith how the law is written is who wouldn't want to vote to prevent the creationof human-animal hybrids? But when we start legislating science fiction, I thinkit sends a poor signal to businesses looking to open operations in Ohio. Someof the legislators here are very open-minded, but some almost see us as anenemy. No matter where the cell source came from, even if it comes from adultstem cells, to some, you are wrong."
 
 
"Stem cell research and the making of hESCs has beenpurposely conflated with abortion," agrees Civin. "In my mind, it has nothingto do with abortion. It's all about noise and votes. It has nothing to do withfacts."
 

Amy Swinderman

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