Feb. 10 -03
Scientists say they have, for the first time, genetically manipulated human stem cells - a first step toward turning the body’s so-called master cells into a useful tool.
USING THE method that made the laboratory mouse so valuable to genetic researchers, the team at the University of Wisconsin deleted a disease gene from human embryonic stem cells. They now have a way to help control how the cells develop, so they can direct them to become brain tissue, or perhaps heart cells or pancreatic cells, said Dr. Thomas Zwaka, who conducted the study with stem-cell expert James Thomson.
GENETIC MANIPULATION “It allows us to manipulate every part of the human genome that we want,” said Zwaka, a doctor and molecular biologist. Thomson’s lab was the first in the world to produce human embryonic stem cells. They are taken from very early embryos left over from couples’ attempts to have test-tube babies at fertility clinics.
[What are stem cells?] What are embryonic stem cells?] [What are adult stem cells?] [How do embryonic and adult stem cells compare?] [Where do the embryos used in research come from?] [What are the possible medical uses for stem cells?] [Are there other potential uses?]
Stem cells are master cells that have the ability to differentiate into other cell types, including those in the brain, heart, bones, muscles and skin.
Embryonic stem cells are cells contained in embryos that have the ability to transform themselves into virtually any other type of cell in the body. It is this quality that enables the tiny embryo to develop into a fully formed body. About five days after fertilization, the human embryo becomes a blast cyst — a hollow sphere of about 100 cells. Cells in its outer layer go on to form the placenta and other organs needed to support fetal development in the uterus. The inner cells go on to form nearly all of the tissues of the body. These are the embryonic stem cells used in research.
Adult stem cells The name is a misnomer because they are harbored in mature tissue in the bodies of children as well as adults. Adult stem cells are more specialized than embryonic ones and give rise to specific cell types. The mature body uses these cells as “spare parts” to replace other worn out cells. For example, certain stem cells in the bone marrow spawn red blood cells, white blood cells and blood platelets. Recent research has suggested adult stem cells can turn into many more cell types than once believed possible.
Embryonic stem cells boast two important qualities: they can become almost anything in the body and they can be grown in culture in an unlimited quantity. The disadvantages are that a patient’s immune system might reject transplants of embryonic stem cells just as some organ transplants are rejected, and that runaway growth of embryonic stem cells could produce tumors. Because adult stem cells would be taken from the very patient who would receive them later in treatment, there are no rejection issues. Disadvantages in adult stem cells include: doubts about whether they can transform themselves as readily as embryonic stem cells; difficulty in growing them in culture at the quantity needed to facilitate transplants, and worry that years of exposure to toxins, radiation and DNA replicating errors could leave them with genetic abnormalities.
Scientists generally harvest embryonic stem cells from embryos left over in fertility clinics after in vitro fertilization procedures. When people undergo IVF, there are usually many more embryos created than can be implanted. Sometimes surplus embryos are discarded; other times, they are donated to help other infertile couples or for research.
Scientists hope to harness the transformational qualities of stem cells to provide treatments for a variety of diseases affecting millions of people worldwide. Because stem cells can turn into many other cell types with the right prompting, doctors may be able to replace tissues and organs damaged by disease or injury to restore healthy function. Therapeutic applications of stem cells potentially could treat illnesses including: Parkinson's disease; diabetes; Alzheimer’s disease; stroke; heart attack; multiple sclerosis; blood, bone and bone marrow ailments; severe burns by providing skin grafts; spinal cord injuries, and cancer patients who have lost cells and tissue to radiation and chemotherapy. In addition, stem cells could be harnessed and packaged to deliver gene therapies to specific targets in the body to treat genetic problems.
Stem cells could allow drugs to be more easily tested without using a laboratory animal as a proxy, as researchers could grow pure populations of specific cell types involved in certain diseases. Then these cells would act as a proving ground for drugs. Ramped-up stem cell technology would permit the rapid screening of thousands of chemicals.
Sources: Reuters; University of Wisconsin, Madison
Extracted when the fertilized egg has divided just a few times, each cell still “remembers” how to become any kind of cell in the body. Once they get older, cells are programmed and cannot easily change direction in development.
The hope is that these cells can be used to replace the brain cells destroyed in Parkinson’s disease, the cells that die in type-I diabetes or cells in damaged spinal cords. But so far it has been hard to program these cells. Zwaka, whose work is published in the journal Nature Biotechnology, said this method will now help scientists do that.
“You can purify tissues,” he said. One problem with human embryonic stem cells is they tend to remember a little too much, and they can form a random mass known as a teratoma instead of the desired tissue. With this method, the genes can be manipulated so as to control the kind of tissue the cells form.
Zwaka’s team is already trying this with the dopamine-producing brain cells that die off in Parkinson’s, an incurable and fatal brain disease that eventually paralyzes victims. The method could also be used, Zwaka said, to create “universal” donor batches, or cell lines, of cells. The genes that cause the body’s immune system to reject foreign tissue could be removed. “You could transplant this line into any patient,” Zwaka said.
BYPASSING CLONING This method could bypass the need for therapeutic cloning — another promising but unproved method that involves taking a cell from a patient using cloning technology to make a very early embryo, and then extracting the cells from it for a personalized transplant. “It is an important alternative,” Zwaka said.
Many people oppose therapeutic cloning on ethical grounds, saying the human embryo created in the process is a life and that destroying it is immoral. A bill pending in Congress and backed by President Bush would outlaw all forms of cloning, including therapeutic cloning. Bush has also severely restricted the use of the embryonic stem cells, which are used by Zwaka and Thomson. Their new method, for which they are seeking a patent, would offer a way to use already-existing batches of the cells. A more immediate use will be in basic science. The method used by Zwaka’s team is called homologous recombination, and it is used to create so-called knockout mice. Advertisement
Scientists can remove genes one by one from mice and see what happens to them. It is often useful for studying human disease — but not always. One example is Lesch-Nyhan disease, a rare type of mental retardation caused by a single genetic defect in boys. “People wanted to study this gene in mice,” Zwaka said. But when mice were engineered to lack the same gene that causes the disease in humans, they seemed perfectly fine. Now the basic molecular mechanisms behind the disease can be studied in human cells, he said.
DESIGNER BABIES NEXT? One big question is whether the method could be used to make designer babies. If genes can be deleted from or added to mice, why not humans? Zwaka said this is impossible to do with existing technology and also undesirable. “You’d have to recreate the entire baby from embryonic stem cells,” he said. “No one knows how to generate a human out of embryonic stem cells and who wants to do that?”
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