Biotechnology research to grow from embryonic start

Wednesday, 6 September 2000

The Adelaide-based biotechnology company, BresaGen, expects to receive human embryonic stem (ES) cells in the near future from the University of Wisconsin, USA. The cells are intended for use in the BresaGen Cell Therapy Programme which is conducted in the Department of Biochemistry at Adelaide University under the scientific direction of Professor Peter Rathjen.

Stem cells are embryonic cells, among the first to appear as a fertilised egg develops. They have the ability to develop into most of the specialised cells in the human body including blood, skin, muscle and nerve cells They also have the capacity to divide and proliferate indefinitely in culture.

Scientists can use these two unique properties of stem cells to produce seemingly limitless supplies of most human cell types from stem cells, paving the way for the treatment of diseases by cell replacement. In fact, cell therapy has the potential to treat any disease that is associated with cell dysfunction or damage, including stroke, diabetes, Alzheimer's and Parkinson's diseases, heart attack, spinal cord injury, cancer, and AIDS.

Parkinson's disease provides a model of how such treatment might occur. The disease is caused by dysfunctional nerve cells in a particular area of the brain. Using cell therapy, these faulty cells could be replaced with healthy, stem cell-derived nerve cells.

"Scientists in the Cell Therapy Programme have been able to produce nerve, muscle and blood cells from mouse ES cells and would like to demonstrate the same transitions using human ES cells," said Dr Paul Tolstoshev. "BresaGen is focusing on developing cell-based therapies for Parkinson's Disease and genetic diseases of the bone marrow, using the mouse and rat as model systems," he said.

The most useful population of human stem cells for therapeutic purposes are the embryonic stem cells. In December 1998, two USA research teams announced the isolation and stable regeneration of human ES cells in culture. Despite the great promise offered by these cells, their source and acquisition raised important ethical questions. These human ES cell lines have come from two different sources. One line was isolated from human foetal tissue obtained from terminated pregnancies, the other was obtained from surplus early-stage human embryos donated by individuals undergoing IVF treatment. It is cells from this second line that Bresagen will use.

Despite the fact that both tissue sources were donated with the informed consent of the donors, the destruction of embryos for stem cell isolation has attracted criticism from some pro-life, religious and bioethics groups. The central ethical argument hinges on the status of an embryo.

"The early-stage embryos used for the isolation of human stem cells are no more than six days old and are invisible to the naked eye," said Dr Tolstoshev, Manager of the Cell Reprogramming Division at BresaGen. "Furthermore, these embryos are composed of around 100-200 unspecialised cells and contain no specialised cell types such as those that make up the central nervous system, including the brain," he said.

The isolation of stem cells from human embryos is legally difficult in Australia, but researchers here are permitted to import cells that have been legally isolated in another country. A research group led by Professor Alan Trounson at the Monash Institute of Reproduction and Development recently obtained human ES cells in this way. Once isolated, stem cells can be handled in the laboratory under guidelines similar to those governing other human cell types.

Because stem cells at present must be harvested from embryonic tissue, there is the possibility of an immune reaction when they are implanted into a recipient; an outcome associated with many organ and tissue transplants. There is also difficulty in obtaining sufficient donor cells. Both problems could be overcome if stem cells could, instead, be harvested from the patient that they are used to treat.

Dr Tolstoshev sees the possibility that stem cell technology may develop to this point, at which embryonic cells will not be required. "There is strong evidence for stem cell populations in adult tissues such as skin, blood and brain," he said. "These may have the potential to form many of the specialised cells in the body, but they are very difficult to isolate and grow using current technologies."

However, there are strong indications that researchers may be able to reprogram normal adult cells to form cells of an earlier developmental stage, possibly even to the ES cell stage.

"If we can develop such technology we can avoid the moral and ethical issues," said Dr Tolstoshev, "but it is critical at this stage that we have access to human embryonic stem cells so that we can study the complex biology involved and assess their potential for cell therapy applications."

BresaGen is attempting to derive stem cells from normal adult cells, which would overcome the ethical issues associated with the isolation of embryonic stem cells and provide an immune-compatible source of cells for therapy. The research is following two separate paths.

In the first, adult cells could be coaxed to form stem cell populations by manipulating the cell culture conditions. The alternative route would involve using 'nuclear transfer technology', which was used to produce Dolly, the world's first cloned sheep. This could be done by fusing an adult cell with either an egg cell, or with an ES cell, that has had its genetic material removed, and then using the resulting stem cells to derive specialised cell types for therapeutic applications.

Although nuclear transfer technology has been used to clone several species including sheep, pigs, goats, cows, and mice, there is no evidence to suggest that the technology can be extended to humans. Furthermore, there is a world-wide ban on human reproductive cloning, and the majority of scientists, government authorities and bioethicists agree that human cloning would offer no benefit to society.

A cell that is recently fertilised is termed totipotent, meaning that it has the unlimited capacity to develop into all postembryonic tissues. As the cell develops and divides repeatedly, this potential is briefly retained. Identical twins develop at the stage when the initial egg has divided into two cells, each of which forms a person.

Normally, however, the divisions occur repeatedly within the single embryo, and as they increase in number, some of the developmental potential of the cells is lost. Once the developing embryo has formed a hollow ball of cells, a cluster of them inside are termed pluripotent. These pluripotent cells can not form a placenta and its supporting tissues, so they can not develop into a complete organism, but they can form virtually all the tissues of the human body.

Several private companies own patents protecting different aspects of stem cell therapy. Geron, a biotechnology company based in California, owns substantial Intellectual Property relating to the identification and use of human pluripotent cells, and methods for the isolation and regeneration of human embryonic stem cells.

It is likely that other complementary technologies will also be required to develop stem cell-based therapies. BresaGen has exclusive rights to a patent application which claims an intermediate cell type (EPL cell) that shares most of the characteristics of embryonic stem cells, but can be more easily coaxed to form specific cell types. The therapeutic uses of this cell type and its derivatives are also claimed in the application. The patent application was filed by Adelaide University and was acquired by BresaGen in 1999.

Contact Details