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The promise, the pitfalls and a paradigm shift, PART 1
To the powerful Michael J. Fox Foundation for Parkinson's Research, stem cell research gives scientists a "pathway" to fighting the devastating effects of—or even curing—Parkinson's disease. To others opposed to one form of stem cell research—the approach that uses human embryos—it "devalues and violates human life," as Pope John Paul II once said.
How these parties arrived at these diverging conclusions about stem cell research is the product of scientific discoveries meeting with changing public discourse, but the one constant in the evolution of this burgeoning area of research is the promise it holds for human health. But although billions of dollars have been spent in the quest to realize this promise, thousands of patents have been issued on stem-cell related technologies and hundreds of companies have been impacted in some way by stem cell research, it is still a scientific field with many hurdles to overcome and divisive concerns yet to be addressed.
In this, our first installment of a three-part series on stem cell research, we explore the history and evolution of the field, what progress 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 Alexander Maksimov found that certain cells could generate blood cells. Legend holds that Maksimov—renowned for his experimental work confirming the Unitarian theory of hematopoiesis—poetically coined the term after noting that the stem of a tree gives rise to a variety of branches.
It wasn't until almost a half a century later that this theory 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 and the introduction of nuclear weapons that scientists picked up where Maksimov and his colleagues left off.
"There was a tremendous amount of concern raised, particularly in the United States and Canada, about understanding the nature of radiation 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 early 1960s, when University of Toronto researchers Ernest Armstrong McCulloch and James Till injected bone marrow cells into irradiated mice, and proved that visible nodules observed in the spleens of the mice arose from a single marrow cell.
In the next two decades, other researchers discovered the pluripotent tendencies of these cells, or their ability to differentiate into many different cell types. Then, in 1981, two groups derived embryonic stem cells (ESCs) from mouse embryos: Martin Evans and Matthew Kaufman from the University of Cambridge, and Gail R. Martin from the University of California, San Francisco.
In 1982, Dr. Curt Civin, then an oncologist and now associate dean of research at the University of Maryland School of Medicine, discovered a monoclonal antibody that allowed scientists to identify and purify blood-forming stem cells. Civin's groundbreaking research has resulted in new tools for diagnosing leukemia and purifying stem cells for research and clinical stem cell transplantation.
In 1998, another major breakthrough occurred when the laboratory of James Thomson at the University of Wisconsin-Madison developed a technique to isolate and grow human embryonic stem cells (hESCs) in a cell culture.
"This is the field that became known as developmental biology in the 1990s," says Dr. Deepak Srivastava, director of the Gladstone Institute of Cardiovascular Disease in San Francisco. "This ushered in the era of scientists being able, for the first time, to study the precise function of genes in an animal model. That burst of information in developmental biology formed the basis for modern stem cell biology, which involves taking stem cells and directing them for various regenerative uses."
In 2006, Japanese researchers in the laboratory of Shinya Yamanaka successfully transformed human fibroblasts into pluripotent stem cells using four genes with a retroviral system. Almost simultaneously, Thomson and his colleagues published similar findings involving different genes using a lentiviral system. These cells became known as induced pluripotent stem cells (iPSCs).
The power and the potency
According to the U.S. National Institutes of Health (NIH), these discoveries led to a classical definition of "stem cells," which incorporates two properties: They must be unspecialized cells capable of renewing themselves through cell division, sometimes after long periods of inactivity, and under certain physiologic or experimental conditions, they can be induced to become tissue- or organ- specific cells with special functions.
Within this definition, scientists have a menu of stem cell lines from which to select. Adult stem cells (ASCs), also known as somatic stem cells, are extracted from adult tissue without harm to the subject. ASCs have the ability to differentiate into more than one cell type, but they are often restricted to certain types. Because they are limited in their differentiation capabilities and can be difficult to harvest, most researchers agree that adult stem 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 the blastocyst (or early-stage embryo), are pluripotent, or have the ability to generate all cell types in the body. One of the scientific concerns about ESCs is that they sometimes form tumors.
iPSCs are a type of pluripotent stem cell artificially derived from a non-pluripotent cell (typically an ASC) by inducing a forced expression of specific genes. Because they are similar to hESCs, some researchers believe they may have great therapeutic potential without the controversial use of embryos. However, their full relation to natural pluripotent stem cells is yet to be determined, and since the Yamanaka discovery, some researchers have demonstrated that they may produce immunogenic responses.
Embryonic ethical dilemma
hESCs have been at the center of ethical, moral and social controversy for the better part of the last two decades. Human embryos reach the blastocyst stage four to five days post-fertilization, when they are about the size of a grain of sand and consist of 50 to 150 cells. Because isolating the ICM results in the destruction of the fertilized human embryo, significant ethical issues have been raised.
Until recently, the principal source of hESCs has been donated embryos from fertility clinics. If a woman undergoes in- vitro fertilization, and has fertilized eggs that she does not intend to use, should the donor have the right to consent that these eggs be used for research? Should researchers pay women to donate their eggs—a process that could involve significant risks? These are questions that have persisted since hESCs were first discovered, and 30 years later, society is still working on finding answers—or at least compromising consensus—says Dr. Debra J.H. Mathews, assistant director for science programs at Johns Hopkins University's Berman Institute of Bioethics.
"Science can tell you a lot," says Mathews, who also serves as a senior policy and research analyst for the Presidential Commission for the Study of Bioethical Issues. "In this particular case, science can tell you that given a willing woman and the right circumstances, a human embryo can become a human baby—but science can't say what we owe that entity. That is a philosophical, existential, religious question. Each individual needs to answer that 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 public conversation, and we need to come to an understanding about what all of this means," Mathews says. "We may not come to complete moral agreement, but we can at least come to a political accommodation of how to conduct stem cell research."
The last three American presidents and their colleagues in government have attempted to do just that. In 1995, President Bill Clinton signed into law a measure that prohibited the U.S. Department of Health and Human Services and the NIH from using appropriated funds for the creation of human embryos for research purposes, or for research in which human embryos are destroyed. Called the Dickey-Wicker Amendment, the legislation was actually a rider 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 if the cell lines were derived prior to Aug. 9, 2001 from an embryo created for reproductive purposes and no longer needed. In addition, informed consent was required for the donation of the embryo, which could not involve financial inducements.
On June 20, 2007, Bush put teeth into that announcement by issuing Executive Order 13435, "Expanding Approved Stem Cell Lines in Ethically Responsible Ways." The order provided for the government support of "research on the isolation, derivation, production and testing of stem cells … derived without creating a human embryo for research purposes or destroying, discarding or subjecting to harm a human embryo or fetus."
"What happened in 2001 and during the Bush years was that only previously existing cell lines could be used for federally funded research—and this created an issue for people who felt that better cell lines had to be developed," Scadden recalls. "The federal government is the biggest driver of research in this area because it is so early in the field, so these events shut off a lot of work. One could try to find philanthropic donors, but that is usually not a resource that is as durable as government grants."
On March 9, 2009, President Barack Obama—as one of his first acts as the nation's newly elected leader—issued Executive Order 13505, "Removing Barriers to Responsible Scientific Research Involving Human Stem Cells," an action intended to reverse Bush's policy. The order was quickly followed by new NIH guidelines for hESC research and its December 2009 approval of 13 human stem cell lines for research.
But these events did not have the impact some expected. According to market research firm Frost & Sullivan, NIH funding for stem cell research has traditionally been low. Although the field saw a sharp rise in hESC research funding in 2008 and 2009 after Obama's order was handed down, Frost & Sullivan notes that funding for both embryonic and non-embryonic research has plateaued at $100 million and $350 million, respectively.
"Interestingly, despite the economic crisis and government cutback in research funds, funding for both non-embryonic and embryonic stem cell lines has risen or remained constant, but has not fallen," says Jonathan Witonsky, industry manager of Frost & Sullivan's Drug Discovery Technologies & Clinical Diagnostics division.
Researchers also benefited from the $20 million to $40 million in economic stimulus funding provided by the American Recovery and Reinvestment Act (ARRA) in 2009 and 2010, the firm adds.
Despite these actions, Mathews notes that Dickey-Wicker remains an obstacle for federally funded researchers seeking to create their own stem cell lines, as Congress has renewed it every year without substantive changes.
"The NIH's guidelines aren't so prescriptive that nothing will meet the bar," she says. "But so far, Congress hasn't had the political will to get rid of Dickey-Wicker."
A will and a way
While legislators may lack the appetite to tackle this debate, plaintiffs in lawsuits filed at every court level are seeking the last word on the use of embryos in stem cell research. Some have failed and some are still proceeding, but at least one case has researchers squirming, as it its ultimate 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 of Columbia, alleges that Obama's executive order violates Dickey-Wicker. The suit's lead plaintiffs, adult stem cell researchers Dr. James L. Sherley, a biological engineer at Boston Biomedical Research Institute, and Dr. Theresa Deisher, research and development director at AVM Biotechnology LLC in Seattle, also argue that Obama's order has intensified competition for the limited government dollars, making it more difficult for them to get funding for their own work.
In August 2010, the court, finding merits in the plaintiff's filings, issued a preliminary injunction that brought federal funding for embryo-destructive research to a halt. A month later, the U.S. Court of Appeals temporarily suspended the injunction as the case moved forward. On April 29, the court completely reversed the ruling on the grounds that it may impose a substantial hardship on stem cell researchers who have multi-year projects already underway.
Interestingly, the court also interpreted Dickey-Wicker to mean that hESC research is permissible under its current language—as Congress has renewed the amendment every year with the knowledge that it funds such research.
But given the facts presented in this controversial case, some legal analysts predict that the last word on Dickey-Wicker may ultimately come in 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 Supreme Court, I'm a little worried because the Supreme Court has been ideologically split on recent issues. The court could interpret Dickey-Wicker to mean that hESC research is illegal."
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 cell research may be conducted and publicly funded.
Some states, such as California, not only allow, but encourage stem cell research in all of its forms. In 2002, Gov. Gray Davis signed into law Senate Bill 253, a measure that explicitly allows research on stem cells from fetal and embryonic tissue. Two years later, California voters approved Proposition 71, creating a $3 billion state taxpayer-funded institute for stem cell research, the California Institute for Regenerative Medicine.
Other states—many of which are known biotechnology hubs—showing support for all forms of stem cell research include Connecticut, Florida, Illinois, Maryland, Massachusetts, New Hampshire, New Jersey, New York, Pennsylvania, Texas, Washington and Wisconsin.
However, several states have imposed or are considering additional restrictions 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 in its statutes. Researchers are permitted to conduct hESC research, but they must not derive any new cell lines. Thus, Michael Gilkey, acting executive director of the National Center for Regenerative Medicine (NCRM)—a multi-institutional center composed of investigators from Cleveland's Case Western Reserve University, the Cleveland Clinic and University Hospitals Case Medical Center—notes that Ohio researchers never benefited from Obama's more liberal funding policy.
"Federal and state laws affect stem cell research, and politicians need to be careful when enacting laws that restrict and criminally penalize researchers," Gilkey says. "The cost alone to monitor and prosecute this would be prohibitive in this economic environment. I think if Ohio follows federal guidelines presented by the National Institutes of Health and does not move to restrict specific areas of research, we'd have more economic development in Ohio. One of our goals is to create a stem cell research and commercialization hub here in Northeast Ohio. More research means new jobs, new revenues and new taxes. We just need the right environment to succeed."
Gilkey says Ohio researchers continue to educate legislators seeking to ban hESC research, human cloning and the creation of animal-human hybrids.
"You can't create human-animal hybrids like you see in science fiction—the genome just doesn't work that way," he says. "The problem with how the law is written is who wouldn't want to vote to prevent the creation of human-animal hybrids? But when we start legislating science fiction, I think it sends a poor signal to businesses looking to open operations in Ohio. Some of the legislators here are very open-minded, but some almost see us as an enemy. No matter where the cell source came from, even if it comes from adult stem cells, to some, you are wrong."
"Stem cell research and the making of hESCs has been purposely conflated with abortion," agrees Civin. "In my mind, it has nothing to do with abortion. It's all about noise and votes. It has nothing to do with facts."