4/28/2009 Eric Schoeniger

Full Stem Ahead

Members of the F&M community explore the technology---and the controversy---that could revolutionize medicine.

On March 9, with a single looping signature, President Barack Obama removed restrictions on federal funding for embryonic ?stem cell research. The restrictions had been put in place in 2001 ?by President George W. Bush, who cited moral concerns about ?the destruction of human embryos.

Obama’s executive order came just weeks after the U.S. Food ?and Drug Administration approved the world’s first tests in humans ?of a therapy derived from human embryonic stem cells. The clinical trial will involve eight to 10 people who have recently experienced ?a severe spinal-cord injury. Researchers will turn embryonic stem ?cells into a type of neural support cell and inject those cells into ?the spinal cord at the site of the injury. The primary goal is to test ?the safety of the therapy. But it also is hoped that the injected cells will restore the ability of some nerve cells to carry signals and even ?spur damaged nerve cells to regenerate.

The new executive order and the newly approved research shine ?a brighter spotlight on a field of study that many scientists say ?will revolutionize medical research and treatment. They also stir ?up a hornet’s nest of controversy.

“There’s a lot of hope that stem cells will be able to cure a wide range of diseases, from genetic diseases to HIV,” says Ryan Mehl, assistant professor of biochemistry. “We’re at a stage where no one can define the limits. That’s part of the excitement, as well as part of the ethical concern. Because when you don’t know the limits of a technology, you have a lot of hope, but you also have a lot of fear.”

Bred in the Bone

Embryonic stem cells are derived from an embryo four ?or five days after fertilization, when the embryo consists ?of about 150 cells. Embryonic stem cells are “pluripotent,” which means they can differentiate into all 220 types of cells in the human body. And that’s what has researchers so captivated. What if we could direct those stem cells to create insulin-producing pancreatic cells to treat diabetes or dopamine-producing neurons to treat Parkinson’s disease or cardiac cells to treat heart disease?

But while stem cell technology sounds like something ?from the distant future, stem cell treatments are hardly new. Bone marrow transplants, which have been performed since the 1950s, are essentially stem cell therapy, wherein transplanted hematopoietic stem ?cells give rise to blood cells.

Although bone marrow transplants are expensive, ?risky and reserved for patients who have life-threatening ?blood cancers such as leukemia, they are becoming ?more common. And doctors are beginning to use ?bone marrow to treat a broader range of conditions.

Last June doctors in Barcelona transplanted the first “tissue-engineered” trachea, using the patient’s own stem cells. Claudia Castillo, a 30-year-old mother of two, had suffered life-threatening collapsed airways from a severe case of tuberculosis. A segment of trachea that would ?act as a scaffold was taken from a cadaver and stripped of cells that would be rejected by Castillo’s immune system. Stem cells from Castillo’s bone marrow were then manipulated to become cartilage cells and used to seed the inner and outer lining of the donor trachea. Today Castillo has a normal quality of life—without the need ?for immunosuppressive drugs.

At Franklin & Marshall, Mehl is working with the Clinic for Special Children to explore the use of bone marrow transplants to treat genetic diseases in the Amish community. One such disease is GM3 synthase deficiency, a genetic mutation that appears in the first months of life and results in a general vegetative state. “It’s a genetic disease, there’s no known cure, and the child is going to die,” Mehl explains. “We think the best solution may be ?a bone marrow transplant when the child is very young.”

In the Beginning

But while bone marrow is more readily available than embryonic stem cells, it is limited in its application. That is just one reason researchers have focused on stem cells derived from embryos.

“Embryonic stem cells are in an undifferentiated state. With the proper cues you can direct them to form virtually any type of tissue,” says Clara S. Moore, associate professor of biology. Moore has conducted research on embryonic stem cells in mice as a fellow at Johns Hopkins University School of Medicine and as a professor at F&M. “So you could create heart tissue to treat heart disease?or neurons to treat a spinal cord injury.”

Moore is quick to point out that stem cells cannot be ?used to build entire organs. “You can culture embryonic stem cells and add certain molecules so that you end up with cardiac cells or neurons,” she says. “But you don’t make a heart; you don’t make a brain.”

In fact, many researchers insist that the promise of embryonic stem cells lies less in direct treatment than in the understanding of disease. “Many years, if not decades, of research are still needed to realize the full utility of embryonic stem cells in the treatment of disease,” says Matthew Renda, Ph.D.,‘96, a research scientist at PGxHealth, which develops genetic tests to help doctors customize drug therapies for individual patients. ?“More important to the research community and likely ?to be more fruitful is the use of embryonic stem cells ?to create disease-specific cell types that can be used ?to study disease mechanisms.”

An example is research Renda conducted in his previous job as a research scientist at the Yale Stem Cell Center, where he used stem cells to explore the role of genetic mutation in a rare form of infant leukemia. The leukemia is believed to result from the fusion of two genes that causes an overproduction of megakaryocytes—bone marrow cells that generate platelets. The lab has received a Connecticut Stem Cell Research Grant to use human embryonic stem cells to derive megakaryocytes in both the presence and the absence of the fused genes, to determine whether the fusion does in fact cause leukemia. The lab favors embryonic stem cells, as opposed to adult hematopoietic stem cells, because it is assumed that the genetic insult ?for this type of leukemia occurs in utero.

Embryonic stem cells also can be used by pharmaceutical companies to screen their vast drug libraries.

“Let’s say you want to measure drug toxicity in liver cells,” Renda explains. “You could use embryonic stem cells to generate a large supply of liver cells and then screen your library of two million compounds to help determine which are safe and which aren’t. Alternatively the cells could be used to identify efficacious compounds in your library.”

Embroiled in Controversy

Where do such embryonic stem cells come from? Obama’s executive order notwithstanding, it is still illegal in the United States to create embryos specifically for ?the purpose of research.

Instead, the embryos used in stem cell research are left over from in vitro fertilization (IVF). Fertility clinics typically culture about a dozen embryos per couple. In most cases, one to four of those embryos are transferred to the uterus, while the rest are frozen. There are at least 400,000 “surplus” embryos currently stored in U.S. clinics. The owners of these embryos can pay to keep them frozen, donate them to other people for use in IVF or discard them. They also can allow them to be used for research.

But creating a line of embryonic stem cells requires ?an embryo to be destroyed. And that has some people fuming. “For those who believe that human life begins ?at fertilization, destroying an embryo is destroying a life,” Moore says.

“There are two concerns people have about embryonic stem cells,” says David Merli, assistant professor of philosophy. “The first is about the moral status of the embryo itself. If you believe an embryo is human life or has the same moral significance as an adult human or has some degree of moral importance, then you’ll be troubled by the destruction of embryos for research purposes.

“The second is about where this research might lead us,” he continues. “You might think that research on embryos is all right in itself but that it might lead us one step closer to research that is morally problematic or might undermine our respect for human life in other contexts.”

On one side of the debate are people who believe ?an embryo should be regarded as a person—because ?it is a person, or because it has the potential to become ?a person, or because it is a part of human life. On the other side are people who think an embryo is simply ?a mass of cells. In the middle—where surveys seem to indicate the majority lies—are people who “argue that an embryo is neither just a lump of cells nor just like a person, ?but a special kind of thing that deserves a special kind ?of respect,” Merli says.

Just as there are moral concerns about embryonic stem cell research, there are ethical questions about therapies that could result from it. For starters, people who oppose the destruction of an embryo to create stem cells might not feel comfortable taking advantage of a treatment ?that uses embryonic stem cells.

In addition, because stem cell treatments are just emerging, there are serious safety concerns—exactly what the FDA-approved spinal cord study is intended to examine. Scientists use chemical cues to direct stem cells to differentiate into a specific cell type. “Those cues are critical, because you have this population of cells that has the potential to divide and keep dividing,” Moore explains. “If any of those cells aren’t directed properly, ?they can form tumors.”

And as with many complex topics, the moral issues surrounding embryonic stem cells can get murky.?“If you believe that embryos have the same moral value ?as adult humans, then even letting frozen embryos be thawed out and destroyed is problematic,” Merli says. ?“But there are ways we think about reproduction that suggest many people don’t take that idea seriously.” ?For example, studies show about one-half of fertilized ?eggs do not implant during the course of normal, traditional human reproduction. “We’re not outraged ?by that,” Merli contends. “That suggests that many ?people aren’t fully convinced that an embryo has ?the same moral status as an adult human.”

Merli points out that an embryo shares some features ?with an adult human but lacks others. “For example, it has a unique genetic identity and it has the potential for life,” he says. “But it doesn’t have properties like consciousness or rationality.” Merli believes the debate around embryonic stem cell research is so compelling, in part, because it raises fundamental questions. ?“It gets us thinking ?about a hard philosophi-cal problem, which is, ‘Why do creatures like ?us have moral value in ?the first place?’”

  • lab

Something Old, Something New

Recent developments in stem cell technology may render much of the controversy moot. In the past few years, scientists have found ways to take adult stem cells, dedifferentiate them back to a pluripotent state, and then redirect them to form new types of cells. These so-called induced pluripotent stem (iPS) cells may one day obviate the need for embryonic stem cells—and the need to destroy embryos for stem cell research and treatments.

To create an iPS cell, scientists might start with a mature skin stem cell. They insert a few key genes to strip the ?cell of its “skin cell” characteristics. They then apply chemical cues so that it forms another type of cell, ?such as a heart muscle cell.

The key genes are delivered through what are called ?“viral vectors,” Renda explains. “Researchers have harvested the ability of certain viruses to permanently deliver genetic information to target cells, a process normally used during viral replication. By genetically engineering safer versions of normally pathogenic viruses, dedifferentiation genes can be programmed into these viral vectors, and this new genetic cargo can be delivered to normal cells, such as skin cells. The delivered genes then cause these cells to dedifferentiate into a more embryonic state that yields iPS cells.”

Last May researchers at UCLA grew beating heart cells from mouse skin cells that had been reprogrammed into pluripotent cells. It was the first study to show that iPS ?cells could be differentiated into the three types of cardiac cells needed to repair the heart and blood vessels.

One potential advantage of iPS cells over embryonic stem cells is that they could be used for “autologous transplants.” Doctors could take cells directly from ?a patient and reprogram them to become the desired tissue—without ?the risk of rejection.

Another advantage ?is that they could be used to study disease development. For example, researchers could take ?a cell from a person with Parkinson’s disease and watch it develop from its embryonic state into a mature neuron. That would allow them to observe key steps in the disease process—?and, potentially, uncover targets for treatment.

There are downsides. The target cells are genetically altered, which can damage chromosomes, and studies have shown that viral vectors can cause cancer by integrating in the wrong place. In mice, embryonic stem cells can generate a new mouse clone; so far, iPS cells ?have failed, suggesting that they differ in some way ?from their embryonic counterparts. So iPS cells might ?be better suited as a source of disease-specific cell ?lines for research than for direct therapeutic purposes.

But the jury is still out. Late last year researchers found ?a way to generate iPS cells from human skin cells without using viral vectors, alleviating some safety concerns. ?And in a stunning achievement, researchers at the Harvard Stem Cell Institute, working with mice, were able to change a type of adult pancreatic cell that doesn’t produce insulin into one that does—completely bypassing stem cells.

These advances have come far faster than most experts expected. And some scientists concede they were driven, ?in part, by Bush’s restrictions on embryonic stem cell research. “We’re getting to a point where we can probably soon move past relying on embryonic stem cells,” Mehl says. “You could argue that the Bush administration ?was correct in saying, ‘If we don’t allow scientists to ?use embryonic stem cells, they’ll find another way.’”

Holy Grail?

But Renda, for one, is not so sure. Like many scientists, ?he believes the federal funding restrictions were harmful. “The Bush administration’s restrictions…have greatly hampered this much-needed research in the United States,” he contends. “Countries such as China, England, Australia, Japan, South Korea and India, where embryonic stem cell research has been allowed, have gained an edge on what ?is surely an area holding much promise and potential.”

Advocates point out that federal dollars are the primary source of funding for basic research in the United States. But during the past eight years, the National Institutes of Health awarded only $300 million for research on the Bush-approved cell lines, out of a $28 billion annual budget. Labs have had to purchase duplicate equipment for embryonic stem cells, reorganize teams after losing members to other countries and scramble for non-federal research funding.

And embryonic stem cells still might be the most useful for research and treatment. “Adult stem cells can be difficult to obtain, they’re harder to purify, and they require extensive manipulation to become other cell types,” Renda concludes. “Embryonic stem cells are still the Holy Grail.”

For the foreseeable future, we likely will remain enmeshed in a debate over embryonic stem cells. Many believe ?it is a debate that should involve everyone.

“In thinking about the ethical issues around stem cell research, you need to be properly informed of the scientific facts,” Merli says. “But just knowing the scientific facts doesn’t by itself determine the answers to the ethical questions. So everyone—scientists, philosophers, policy-makers, citizens—has an interest in this. It’s hard to imagine the genie’s going to stay in the bottle.”


Vive la Differentiation

Stem cells are found in most multicellular organisms. They are characterized by the ability to differentiate into a range of specialized cell types and to renew themselves by continually dividing.

Adult stem cells are undifferentiated cells found in bone marrow, the intestinal tract, skin and other parts of the body. They multiply through cell division to replenish dying cells and regenerate damaged tissues. They typically can regenerate only specific types of cells. For example, stem cells found in bone marrow are best at producing blood cells.

Embryonic stem cells, in contrast, occur in the inner mass of an embryo four or five days after fertilization, when the embryo comprises about 150 cells. They are unique in that they are pluripotent, which means they can differentiate into all 220 cell types found in the human body. They also can make unlimited copies of themselves.

Embryonic stem cells have the potential to replace any cells damaged by or lost to disease or injury. Scientists caution that direct treatments could be years away. But conditions with the greatest potential for treatment include diabetes, Parkinson’s disease, spinal cord injury and heart disease.
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