Stemming the Tide of Disease

Stem Cell Research Holds Promise, Creates Controversy  

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Science Feature -- October 2003

By  Ken Ortolon
Senior Editor

Kidney disease usually means a lifetime of dialysis and eventual placement on the organ transplant waiting list. But what if doctors could simply inject cells into a patient's weakened kidney that would eventually grow into new tissue and improve kidney function? Or, what if scientists could grow a whole new kidney using cells from the patient's own body that could be transplanted into the patient without fear that his or her body would reject it?

Sound farfetched? Well, it's not. Thanks to research into potential uses of stem cells -- some of it here in Texas -- these treatments may become reality within the next decade.

Scientists say the potential medical gains from stem cell research are enormous. "I personally think this is going to revolutionize all of medicine and, hopefully, in a short period of time," said Richard Champlin, MD, chair of the Blood and Marrow Transplant Department at The University of Texas M.D. Anderson Cancer Center in Houston, and a stem cell researcher. "It may be a major turning point for medical therapies, in general."

But stem cell research is highly controversial. Conservative Christians, antiabortion activists, and other groups have criticized the use of tissues from aborted fetuses and frozen embryos produced for in vitro fertilization as the source of stems cells for research. Others say scientists are tampering with the very sanctity of human life and are just a short step away from the slippery slope of human cloning.

The criticism led President George W. Bush to restrict the use of embryonic stem cells in federally funded research. Those restrictions, scientists say, discourage stem cell research in the United States and eventually could drive it off university and medical school campuses.

"What you do when you declare something illegal is you drive it underground, and that's exactly what's happened," said James F. Leary, PhD, chief of the Molecular Cytometry Unit at The University of Texas Medical Branch at Galveston (UTMB).

Differentiating Between Cells

Stem cells have two important characteristics for medical researchers. First, they are unspecialized cells that renew themselves for long periods through cell division. Second, under certain physiologic or experimental conditions, they can be induced to become cells with special functions, such as the beating cells of the heart muscle or the insulin-producing islet cells of the pancreas.

Scientists use stem cells because they "have the potential to amplify, replicate themselves, and to become any type of cell in the nervous system," said Ping Wu, MD, PhD, assistant professor of anatomy and neuroscience at UTMB. "But there is a problem there. They do not become specific types of cells by themselves. You have to lead them to become a specific type of cell."

And, scientists must learn to control their growth, Dr. Wu says. Otherwise, instead of creating a useful amount of new, healthy tissue inside a diseased liver or kidney, you might just create a tumor.

Scientists say Texas is not a hot bed of stem cell research compared with elsewhere in the nation, but a variety of research is happening at the state's medical schools and other facilities.

Dr. Wu and UTMB researchers have worked for more than three years to figure out how to use neural stem cells to regenerate nerve and brain tissue in patients with spinal cord injuries, strokes, Lou Gehrig's disease, or other conditions. Using a technique she invented called priming, Dr. Wu introduces a "protein cocktail" into the stem cells and bakes them in tissue culture dishes. When the cells reach a certain stage, she grafts the cells into rats.

"We transplant the cells into the brain and spinal cord. They stop proliferation and then become specific types of neurons based on where they are implanted," she said. "This has been treated as a breakthrough. Previously, scientists had difficulty getting them to turn into specific types of neurons. We were able to do that. But there is still a long way to go and we will have to address a lot of issues."

Dr. Wu says her team is still trying to determine if the primed cells will become specific types of motor neurons and if they will make the right connection with targeted muscles. If successful, the technique could help cure paralysis caused by spinal cord injuries and help restore motor skills lost because of brain injury, stroke, or degenerative disorders.

Chip Off the Old Gene

Dr. Leary uses stem cells from cord blood to study how HIV attacks the human body. He uses "gene chip" technology to study how the interaction between HIV and the human herpes virus 6 alters the gene expression pattern within stem cells and makes them vulnerable to HIV.

"Normally, HIV does not attack human stem cells, which is why human beings don't immediately get AIDS after HIV infection," he said. "The reason is that the stem cell compartment does not have the receptors to bind the HIV virus. But what we have found is that the human herpes virus 6, which most of us have, does activate receptors on human stem cells. We have some preliminary evidence that it may happen in patients whose immune systems collapse."

Dr. Leary hopes he can "turn on" the right genes within stem cells to protect them from HIV.

"What we hope to accomplish is to protect the stem cell compartment. Every one of those stem cells is worth thousands of lymphocytes that would be destroyed by HIV during AIDS. If we can protect the stem cell compartment, then we can treat the disease at a place where it is not going to cause as much damage, and the patient whose stem cell compartment is not being infected seems to live a lot longer."

At M.D. Anderson, the UT Health Science Center at Houston, and Baylor College of Medicine, researchers are using stem cells to develop new treatments for cancer and heart disease.

Dr. Champlin says M.D. Anderson has used blood stem cell transplantation for several years to treat patients receiving high-dose chemotherapy. "This is sort of the newer version of bone marrow transplantation," he said. "We collect the blood forming stem cells from the blood and use those to help people recover after strong doses of chemotherapy and also to generate an immune response that can kill the tumor."

M.D. Anderson scientists are taking it a step further. They have discovered that blood stem cells actually contribute, at least a little, to forming other body tissues; thus, they may be useful in regenerating skin, lung, heart, or other tissue damaged by cancer or other diseases.

They also are working on delivering interferon or other cancer-fighting proteins directly to tumors. They have discovered that mesenchymal stem cells -- cells that make up the fibrous tissues of the body -- can home in on tumors, which also are fibrous. They hope to genetically modify those cells to produce interferon or other proteins that actually can kill tumors.

Researchers at UT-Houston are working with scientists and physicians in Brazil to regenerate heart tissue in patients who have suffered heart attacks or heart failure. The scientists manipulate stem cells and then inject them intravenously into the patients.

James Guckian, MD, acting executive vice chancellor for health affairs for the UT System, says the process appears to be producing beneficial results. "Those stem cells apparently are going to the heart, and they are differentiating and growing into myocardial cells. In fact, early indications are that some people with heart failure have improved after the injection."

Similar research was conducted at Baylor. In 2001, researchers there announced that stems cells transplanted from the bone marrow of one adult mouse to another could transform into blood vessels and cardiac tissue, and help restore tissue damaged from a heart attack.

Baylor scientists also have examined the role of stem cells in skin disease and the ability of stem cells from bone marrow to transform into brain cells, and have produced blood cells from muscle cells.

The Embryo Debate

As groundbreaking as some of this research is, scientists say the really dramatic breakthroughs potentially are being stalled -- at least in America -- by limits on using human embryonic stem cells in research.

In August 2001, President Bush limited federal funding for human embryonic stem cell research to projects using cells from some 60 previously existing stem cell lines. His decision essentially cut off future use of cells from frozen embryos being discarded by fertility clinics. And, scientists say, most of the 60 cell lines they can use are essentially useless for any human research because they were grown in cultures that include mouse tissue, which could carry viruses that scientists would not want to introduce into the human genome.

Dr. Leary says the policy discourages university researchers from undertaking stem cell research and pushes it into the unregulated commercial sector, where there are no standards. University-based researchers who want to conduct embryonic stem cell research have little choice but to partner with researchers in other countries, where similar limitations don't exist. For example, England has banned human cloning, but permits the use of both embryonic stem cells and somatic cell nuclear transfer for research purposes, he says.

That means most American researchers are now limited to working with so-called adult stem cells, which are derived from other sources.

While embryonic stem cells are derived from the inner cell mass of the blastocyst and appear to have an unlimited ability to reproduce, adult stem cells are more limited in the type of cells into which they can differentiate, says Dr. Leary. Though not harvested from adult human beings or animals, they are called adult stem cells because they come from more mature tissue. A large amount of stem cell research is performed using adult stem cells within the blood of human umbilical cords usually discarded after birth. A growing number of parents are having their baby's cord blood cells frozen as a source of future stem cells for transplantation to treat any diseases the child may develop, Dr. Leary says.

While embryonic stem cells can differentiate into just about any type of cell, adult stem cells can only be "nudged" a little bit from the pathways they're already on, he says. "They're only going to go down certain pathways."

The use of embryonic stem cells has been controversial because of their origin. Even though fertility clinics discard thousands of frozen embryonic cells created for in vitro fertilization each year, antiabortion activists and others consider research on them as taking human life because the embryos must be destroyed to harvest the cells.

Also controversial is a newer process called somatic cell nuclear transfer, in which scientists remove the nucleus from a human egg and insert a nucleus from a human skin or other cell. The egg can grow and eventually produce an early embryo.

Dr. Guckian says UT institutions are not doing human somatic cell nuclear transfer research, but says most scientists believe it will lead to the greatest advances.

But that technology could be perverted for other purposes, such as cloning and eugenics, says Clarke Cochran, PhD, a Texas Tech University political science professor who also lectures on health policy and politics.

"I don't doubt the integrity or sincerity or motives of scientists working in stem cell research," he said. "But it seems to me that embryonic stem cell research treats human life as a product to be used at our disposal, and that's ethically wrong. Human life, from its very beginning, is due a certain amount of respect and a certain amount of dignity because this is something that could grow, could become an adult."

Dr. Cochran also is concerned that scientists will use embryonic stem cells not only to cure disease but also "to make people taller or blonder or more athletic."

"Embryonic stem cell research is not just one isolated thing," he added. "It's connected to genomics, it's connected to cloning, and it's connected to a variety of other actual or potential researches and technologies that carry their own major ethical problems."

Scientists say those concerns are unfounded. Dr. Guckian says stem cell research is never intended for human cloning, and he supports an outright ban on human cloning.

And, human life is not being created or destroyed with somatic cell nuclear transfer, he says. "It's not true fertilization. It is not taking a sperm and an egg to produce another human being. The cells that are going to be produced could never become a human being because they don't have all the information that's necessary to become a human."

Scientists and physicians question whether they can ethically step away from embryonic stem cell research knowing that the answers to so many diseases may lie just ahead.

"Can we ethically not go forward with it knowing that there are so many potential answers to so many diseases?" asked John Jennings, MD, professor of obstetrics and gynecology at UTMB.

But Dr. Cochran says there are limits on what's appropriate even when it comes to curing disease and saving lives.

"Even for good ends there are limits on things that we ought to do. Certainly those limits come into play when we're dealing with the fundamentals of human procreation, the fundamentals of human life, itself."

Ken Ortolon can be reached at (880) 800-1300, ext. 1392, or (512) 370-1392; or by email at Ken Ortolon .

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