Wisconsin scientists culture elusive embryonic stem cells
Nov. 6, 1998
Stem cell images
Human embryonic stem cell colonies in different stages of development. The maintenance of embryonic stem cells in their undifferentiated form is a primary accomplishment of the work reported in the Nov. 6 Science by a team from UW-Madison. Here, embryonic stem cell colonies sometimes include a core of undifferentiated cells surrounded by a margin of differentiated cells, such as the small colony at right in Figure B.
© 1998 Science. (larger version)
The human embryonic stem cells cultured at UW-Madison have been observed to randomly differentiate in culture into a variety of different cell types, including (A) gut, (B) neural cells, (C) bone marrow cells, (D) cartilage, (E) muscle and (F) kidney cells. Although such differentiation occurs spontaneously under certain culture conditions, scientists do not yet know how to direct the development of embryonic stem cells into specific cell types.
© 1998 Science. (larger version)
The dream of one day being able to grow in the laboratory an unlimited amount of human tissues for transplantation is one step closer to reality.
Writing in the journal Science, a team of scientists from UW-Madison report the successful derivation and prolonged culture of human embryonic stem cells — cells that are the parent cells of all tissues in the body.
The achievement has profound implications for transplant medicine, drug discovery and basic developmental biology. It opens the door to growing from scratch everything from heart muscle to bone marrow and brain tissue.
The work "shows you can derive and culture these cells, and it opens the possibility for some dramatic new transplantation therapies," said James A. Thomson, a UW-Madison developmental biologist and the lead author of the report published Nov. 6 in the nation's leading scientific journal. "Although a great deal of basic research needs to be done before these cells can lead to human therapies, I believe that in the long run they will revolutionize many aspects of transplantation medicine."
The work, which was supported by the Menlo Park, Calif.-based biotechnology company Geron Corp., caps a 17-year international race to be the first to capture and sustainably culture human embryonic stem cells. By providing the raw material for virtually every kind of human tissue, new customized strategies for treating a wide range of human diseases including diabetes, heart disease, some forms of cancer, and Parkinson's disease can now be developed.
For example, many diseases, such as Parkinson's and juvenile onset diabetes mellitus, occur because of the death or dysfunction of just one of a few cell types. The replacement of those cells would offer lifelong treatment. To treat heart disease, heart muscle cells could be injected directly to shore up failing heart tissue.
Such clinical applications are years — perhaps more than a decade — away.
The embryonic stem cells were derived from the inner cell masses of donated human blastocysts. A blastocyst is a hollow ball of about 140 cells that develops several days after fertilization. The embryos from which the blastocysts developed were produced in a laboratory dish for clinical purposes, prepared to assist couples having difficulty achieving pregnancy. They were left over after successful clinical procedures to treat infertility, and in cooperation with the UW-Madison Medical School's department of obstetrics and gynecology, were donated specifically for this project with the informed, written consent of the patients.
Thomson's team established five independent cell lines and has been able to grow them indefinitely in culture. They have observed the cells to differentiate into the three primary germ lines that make up the body — endoderm, ectoderm and mesoderm — and subsequently into arrays of tissue cells such as cartilage, bone, muscle, neural and gut cells.
For biologists, these cell lines offer insights into developmental events that cannot be studied directly in the human embryo, but which have important clinical consequences for birth defects, infertility and pregnancy loss, said Thomson. Moreover, a more complete understanding of normal development will ultimately allow the prevention or treatment of abnormal human development.
The most likely immediate application of human embryonic stem cell technology, according to Thomson, would be strategies to quickly screen hundreds of thousands of chemicals for effective medicines. By measuring how pure populations of specific differentiated cells respond to potential drugs, it would be possible to sort out drugs that may be both useful or problematic in human medicine.
The Wisconsin Alumni Research Foundation (WARF), an independent, not-for-profit corporation that manages patents on behalf of UW-Madison, has applied for a patent on the human embryonic stem cell technologies described in today's Science article and Geron Corp. has a license to develop the technology. The company has invested significantly in the long quest for human embryonic stem cells. In addition to supporting the efforts at Wisconsin, it has funded other groups doing similar work at Johns Hopkins University and at the University of California at San Francisco.
Because there is a prohibition on the use of federal money for such research, federal funds were not used to support the stem cell work at Wisconsin.
"Our hope is that these cells could be grown in the laboratory and then used to regenerate failing tissue," said Thomas Okarma, Geron vice president for research and development. "Because these cells do not age, they could be used to generate virtually a limitless supply of cells and tissue for transplantation."
While the Wisconsin scientists have been able to capture and culture undifferentiated human embryonic stem cells, their transformation into different types of cells cannot yet be directed. Under certain culture conditions the embryonic stem cells differentiate, but the differentiation is to a random, mixed population of cells.
Finding ways to direct the human embryonic stem cells to become specific cells of clinical importance is an important next step required before new therapies can be developed.
Ways to prevent the immune system from rejecting transplanted cells also need to be developed. However, banking embryonic stem cells with records of genetic compatibility, or genetically altering cells to reduce or combat immune rejection, are two potential strategies for overcoming the problem, said Thomson.
Thomson's group is now actively pursuing collaborations with clinical scientists and transplant surgeons to perform the basic research needed to ultimately develop human embryonic cell-based therapies. Among those is Jon Odorico, a UW-Madison transplant surgeon, who cited the potential of human embryonic stem cells to be used in very focused ways to repair or replace damaged or diseased tissues or organs.
"The principal theoretical advantages of this type of treatment for organ replacement over current organ transplantation is the fact that the cells can be grown in large quantities, helping to negate the problem of the limited supply of donor organs, and can be genetically engineered outside the body to escape immune attack," Odorico said.
These "experiments have opened up some exciting new areas of research for transplant surgeons," he added.
Co-authors of the paper published today include Joseph Itskovitz of the Rambam Medical Center, Haifa, Israel; Sander S. Shapiro, Michelle A. Waknitz, Jennifer J. Swiergiel, Vivienne S. Marshall and Jeffrey M. Jones, all of UW-Madison.