Exploring a New Frontier: Stem Cell Research at Northwestern

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A colony of embryonic stem cells. The cells in the background are mouse fibroblasts cells. Ryddragyn/WIKIMEDIA COMMONS

Mention stem cell research and most people will have a strong reaction. Some oppose it. Many do not understand it. Others see it as an amazing source of revolutionary medical advancement. Many research scientists and teachers at Northwestern fall into the third group. They have seen the potential of stem cells in treating diseases and conditions such as Parkinson’s, juvenile diabetes, spinal cord injuries, and cancer.

Stem cells are undifferentiated cells that can both renew or replicate themselves and differentiate into other specialized cells. In other words, stem cells can divide indefinitely to provide as much tissue as needed for therapy, and they can be coaxed to develop into virtually any type of body cell.

The science of stem cell technology is fairly new. In 1998 a team of scientists from the University of Wisconsin-Madison was the first to isolate stem cells and keep them alive in the laboratory. Last year two American scientists—Mario R. Capecci of the University of Utah and Oliver Smithies of the University of North Carolina— and Welsh scientist Sir Martin J. Evans from Cardiff University won the Nobel Prize in Physiology or Medicine for their “discoveries of principles for introducing specific gene modifications in mice by the use of embryonic stem cells.”

Origins and Types of Stem Cells
What has pulled this scientific discovery into the headlines so that nearly every American has an opinion about stem cells is their source: human embryos. Embryonic stem cells are derived from a very early stage in human development. These cells are pluripotent, meaning that they have the potential to produce all of the body’s cell types. There also are other types of stem cells: adult stem cells are found in certain tissues in humans and appear to be limited to producing certain types of specialized cells. Recently, scientists also have identified stem cells in umbilical cord blood and the placenta that can give rise to the various types of blood cells.

Embryonic stem cells can be derived in two different ways. One is that, with a donor’s consent, they can be transplanted from frozen embryos stored at in vitro fertility clinics because they are in excess of a recipient’s clinical need. When they are no longer needed for uterine transplantations, they are typically discarded.

The second way of deriving embryonic stem cells is through somatic cell nuclear transfer. This involves removing the nucleus of a donor’s unfertilized egg and replacing it with the nucleus of an adult cell. No sperm is used in this procedure and, thus, there is no fertilization. Embryonic stem cells that have proliferated in cell cultures for six or more months without differentiating are pluripotent. These proliferated cells, if they appear genetically normal, are referred to as an embryonic stem cell line.

Politics and Moral and Ethical Issues
Laurie ZolothLaurie ZolothThe furor arising from the creation of embryonic stem cell lines comes from those who find moral or ethical issues with the cells’ origins and the process and means by which they are derived, explains Laurie Zoloth, bioethics and medical humanities and religion, and director of Northwestern’s Center for Bioethics, Science and Society.

It was the sensitivity to these moral and ethical issues that prompted President George W. Bush’s decision to limit federal funds for research only to stem cell lines made from embryos that were destroyed before August 9, 2001—the day he announced his policy. He claimed there were “more than 60 genetically diverse stem cell lines,” enough “to explore the promise and potential of stem cell research.” Since his ruling, researchers have discovered that all of the stem cell lines derived before August 9, 2001 are contaminated with animal molecules from the culture medium used to sustain them.

Although public opinion now stands at more than 60 percent in favor of greater federal support for this research, the president has twice vetoed the Stem Cell Research Enhancement Act. According to Northwestern scientists who have testified in support of the act, limiting stem cell research has only delayed advances in this science. Therefore, several states have considered legislation or funding mechanisms to support this research and to attract and retain stem cell researchers.

The Illinois legislature passed the Illinois Regenerative Medicine Act in August 2007, permitting the Illinois Regenerative Medicine Institute (IRMI) to conduct stem cell research on cells from any source. In 2006 three Northwestern scientists received IRMI stem cell grants totaling almost $3.5 million: Guillermo Ameer, biomedical engineering; Mary J.C. Hendrix, president and scientific director of the Children’s Memorial Research Center and professor in The Robert H. Lurie Comprehensive Cancer Center of Northwestern University and at the Feinberg School of Medicine; and Xiaozhong A. Wang, biochemistry, molecular biology and cell biology. These researchers and others at Northwestern currently are doing pioneering work on stem cells.

Controlling Malignant Tumor Cells
With support from IRMI and the National Cancer Institute, Hendrix and her colleagues have discovered that a protein governing the development of human embryonic stem cells also inhibits the growth and spread of malignant melanoma, the deadliest skin cancer. The protein, called Lefty, suppresses aggressive breast cancer cells as well. Lefty is secreted predominately by human embryonic stem cells and not by stem cells isolated from amniotic fluid, umbilical cord blood, adult bone marrow and placental cells.

This groundbreaking work by Hendrix and her colleagues is illuminating how aggressive melanoma cells, by becoming more like unspecialized stem cells, gain enhanced abilities to migrate, invade, and metastasize while remaining virtually undetected by the immune system.

Results of the study are described in an article in the March 3 online version of the Proceedings of the National Academy of Sciences.

Repairing Damaged Spinal Cords
In 2005 Northwestern University was named a Center of Excellence in Translational Human Stem Cell Research by the National Institutes of Health, one of two institutions to receive the prestigious NIH Center of Excellence grant. The principal investigator at Northwestern is John A. Kessler, neurology, at the Feinberg School of Medicine.

John Kessler and Samuel StuppJohn Kessler and Samuel StuppKessler directs research on the factors that influence the differentiation of human embryonic stem cells and works on combining unique biomaterials and human embryonic stem cells as a possible means to repair damaged spinal cords. Kessler is working with Samuel Stupp, materials science and engineering, chemistry and medicine, and director of the Institute for Bionanotechnology in Medicine, and his research group on regenerating the spinal cord. The nature of this research requires the marriage of medicine with technology, which is why Kessler and Stupp make such a powerful team.

By injecting molecules that were designed to self-assemble into nanostructures in spinal tissue, they have been able to rescue and regrow rapidly damaged neurons. The nanofibers—thousands of times thinner than a human hair—are the key to not only preventing the formation of harmful scar tissue that inhibits spinal cord healing, but also to stimulating the body into regenerating lost or damaged cells. Similar to earlier experiments that promoted bone growth, the Kessler-Stupp researchers now have successfully grown nerve cells using an artificial three-dimensional network of nanofibers, an important technique in regenerative medicine.

Developing Replacement Blood Vessels
The funding given Guillermo Ameer, biomedical engineering, helps support studies of stem cell-based vascular tissue engineering to develop replacement blood vessels. Ameer and his collaborators believe their research may eventually eliminate the need to harvest existing blood vessels from patients with vascular disease in order to improve the performance of vascular grafts.

For the in vivo approach to tissue or organ replacement, Ameer and his research team develop scaffolds and techniques conducive to the reconstitution or maintenance of normal tissue microarchitecture. Disruption of normal tissue microarchitecture can lead to scarring or degeneration resulting in loss of or impaired function. Thus, they are working with and studying novel biomaterials and processing techniques to produce scaffolds suitable for tissue engineering. In particular they are interested in understanding the effects of scaffold characteristics on cellular and tissue development in order to prevent deleterious processes.

Using Bone Marrow Cells to Treat Autoimmune Conditions
In the Feinberg division of immunotherapy for autoimmune diseases, division chief Richard K. Burt, medicine, leads a multidisciplinary clinic- and laboratory-based program developing ways to use bone marrow stem cells and immune cells to treat conditions such as lupus, multiple sclerosis, rheumatoid arthritis, Crohn’s disease, systemic sclerosis, myasthenia gravis, chronic inflammatory demyelinating polyneuropathy, and autoimmune blindness.

Researchers in this program have used adult stem cell injections to repair the immune systems of patients with early-onset Type 1 diabetes. After the therapy, patients did not require insulin for up to 35 months.

Also in the study, patients with Type 1 diabetes were treated with a high dose of immune suppression drugs followed by an intravenous injection of their own blood stem cells, which had previously been removed and treated. Burt said this is the first time, to his knowledge, that patients with Type 1 diabetes have been treated with their own stem cells.

“I think this treatment helped the body regenerate its immune system,” said Burt, senior author of the study that was published in the Journal of the American Medical Association. In addition, Burt and William H. Pearce, vascular surgery, performed the first stem cell injections into the legs of patients with peripheral vascular disease in the United States and will soon be developing a trial to use umbilical cord blood stem cells for peripheral vascular disease.

Using a Patient’s Own Adult Stem Cells for Treating Blocked Arteries
Douglas LosordoDouglas LosordoDouglas W. Losordo, director of Feinberg’s Cardiovascular Research Institute and director of cardiovascular regenerative medicine at Northwestern Memorial Hospital, is an interventional cardiologist with an established basic science laboratory studying endothelial cell and stem cell biology, angiogenesis, and tissue repair and regeneration. He has launched the first U.S. trial in which a purified form of a subject’s own adult stem cells is transplanted into leg muscles with severely blocked arteries to try to grow new small blood vessels and restore circulation. The first two subjects in the 20-site national trial recently underwent the stem cell transplant process at Northwestern Memorial Hospital.

The Northwestern-led Phase I/IIa study includes 75 people from around the country and targets patients who have exhausted all other medical options—including angioplasty, stents, and bypass surgery—to repair blocked circulation in their legs.

“They’re at the end of the therapeutic road and they're ultimately facing potential amputation,” said Losordo, principal national investigator for the study. “This is hopefully a way to help them avoid that."

“The stem cells themselves can assemble into blood vessels,” Losordo said. “They can also secrete growth factors that stimulate and recruit other stem cells to come into the tissue and help with the repair. It’s an amazing biology we’re trying to leverage in these folks.”

“Northwestern Memorial Hospital has a major clinical program in bone marrow stem cell transplantation,” adds Kessler. “People sometimes forget that bone marrow transplantation is a stem cell therapy that has been used for more than 20 years.” Children’s Memorial Hospital also has an active program in pediatric bone marrow transplantation.

Looking Into How Stem Cells Work
Xiaozhong (Alec) Wang, biochemistry, molecular biology, and cell biology, received funding from the IRMI to investigate genetic control of pluripotency and differentiation in stem cells to control self-renewal and multipotency. Multipotent stem cells can give rise to several other cell types, but those types are limited in number, says Wang. An example of a multipotent stem cell is a hematopoietic, or blood, stem cell that can develop into several types of blood cells but cannot develop into brain cells or other types of cells. At the end of the long series of cell divisions that form the embryo are cells that are terminally differentiated, or considered to be permanently committed to a specific function.

Stem Cell Science Outreach
Ameer, Burt, Hendrix, Kessler, Losordo, Stupp, Wang, and Zoloth are but a few of the many Northwestern research scientists who study stem cells, their origins and applications. Kessler, Losordo and Zoloth were among the speakers who represented the University at a conference held at Northwestern on February 22, the first of several planned nationwide by the Biotechnology Institute and National Academies. More than 100 people—including local high school and junior college educators—gathered to explore the minefields of teaching stem cell technology and other controversial sciences. The effort was sponsored at Northwestern by the Biotechnology Center at the Kellogg School of Management, the Office of STEM Education Partnerships, and the Office for Research Development along with the Chicago Council on Science and Technology and other regional university, industry and state partners.

—reprinted from CenterPiece, Volume 7, Number 2

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Dear Shepherd Center

Dear Shepherd Center I first heard on the news about the first trail of stem cells research. I thought to myself “Wow” I would jump at the chance to voluntary. To be in this predicament having an opportunity to have another chance of life to possible gain some independence back would truly be a blessing. I would like to become a new trial patient for the research of stem cells. You see I am a 32 years old male. I have been a paralyzed for the last 8 years. It is an incomplete spinal injury C5, C6. I am totally disabled, but I don’t let that define me. I was and still am a very athletic guy even if I cannot physical do it. The desire is still in my heart. Back in the day I was sprint runner, cheerleader, and gymnast coach and cheerleader instructor. I’ve won many medals doing these activists. I dream and pray of moving my arms and legs again. I cry often that I cannot move anymore. My parents have to do everything for me, I mean everything. I am willing to undergo any experimental trials, tests, surgeries or medications you will administer. I have tried rehab several times with no results. I still have my whole life ahead of me. I just have to get into your program. Hopefully would consider me to be apart of your trials. Please pick me! I would be so graceful to you if you would select me to be a volunteer for this trail. Cariell Collins

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