ET

We can rebuild you . . .

Bone marrow cells can provide a wide range of tissue to repair an ailing body,
says Roger Highfield

THE possibility that a damaged or diseased organ could be repaired with tissue grown in the lab has increased in the past few days with reports on the science of stem cells, the most talented cells in the body.

Stem cell research is hailed as the start of a medical revolution that will lead to new treatments for diabetes, Parkinson's, Alzheimer's, heart disease and cancer.

The most versatile variety of stem cells is found in embryos. This discovery has triggered concerns that the development of successful treatments could lead to a level of demand that could be met only by the mass production of human embryos by IVF methods or cloning.

Pro-life groups oppose dismantling embryos for their cells, which they liken to human sacrifice. However, recent research suggests that this may never be necessary, as cells in adults appear to be more flexible than anyone thought.

There are many things that scientists don't understand: why, if the body is full of stem cells, doesn't it do a better job of repairing itself? And to what extent are cells born, rather than made? Most people agree that more research on human embryos is needed.

The most controversial source of stem cells is the least controversial in terms of scientific understanding. Every cell in an early embryo, one smaller than the full stop at the end of a sentence, is "totipotent", that is, can give rise to a fully developed organism.

After two days, a totipotent stem cell divides, matures and gives rise to more restricted cells called "pluripotent" stem cells. They give rise to any cell of the body, although they have lost the potential to form an organ, or a fully developed organism. Pluripotent cells, also called embryonic stem cells, can self-renew, so relatively few embryos will be needed for research.

More mature stem cells can be found within the organs. These "multipotent", or adult, stem cells were not thought to live as long or be as viable as pluripotent cells.

One example is reported in the current issue of Nature. Prof Fred Gage of the Salk Institute, La Jolla, found that multipotent cells can be grown from post-mortem brain material after adding growth factors.

His team studied samples taken during post-mortems on 15 cadavers and obtained functioning cells up to 20 hours after death. Importantly, recovered cells had the ability to differentiate into different types: neurons, the cells that form the "wiring" of the nervous system; astrocytes, which nourish and protect neurons; and oligodendrocytes, which insulate neurons.

"I find it remarkable that we all have pockets of cells in our brains that can grow and differentiate throughout our lives and even after death," said Prof Gage.

The work raises hopes that such cells, like organs, could one day be taken from the dead - or living brain biopsies - and given to sufferers of neuro-degenerative diseases such as Parkinson's. "Or we could learn to activate the remaining cells in the brain to divide and replace the missing or damaged cells in what is being termed self-repair," he said.

In recent years, scientists have started to question long-held beliefs about the limitations of adult stem cells. It had been thought that adult bone marrow stem cells were committed only to making blood cells.

A number of studies have shown that these cells have surprising plasticity. They can transform themselves into mature cells of other organs such as skeletal muscle, bone and brain.

A bone marrow stem cell that can transform itself into almost any tissue type has been reported in the latest issue of Cell by Dr Neil Theise of New York University, Dr Diane Krause of Yale University and Prof Saul Sharkis of Johns Hopkins School of Medicine.

Prof Sharkis purified bone marrow cells of male mice and took a single cell for transplant into female mice that had their bone marrow destroyed by radiation. Eleven months later, the team found male cells in the blood and bone marrow of the surviving female animals, using colour dyes that light up the Y (male) chromosome.

Through these homing studies, Theise and Krause found the male chromosome not only in the bone marrow and blood, as expected, but also in the tissue from the lung, oesophagus, stomach, intestines, liver and skin.

The Cell study provides the strongest evidence yet that the adult body contains stem cells that are as flexible as embryonic stem cells. "It's astounding that there are cells in our bone marrow that can become so many different cell types - including blood, lung, GI tract and skin," said Dr Krause.

But she stressed that the new findings do not mean that research on embryo stem cells should be abandoned.

"Because this field is very much in its infancy, we need to keep working with embryonic stem cells, " she said. Other scientists endorse this view on the grounds that embryonic stem cells may have better growth potential in the lab, for example.

Further work is needed to find out whether all types of adult stem cells are as talented, or whether bone marrow alone has super stem cells, since it can easily dispatch them to any part of the body via the blood circulation.

But that raises another question: if bone marrow stem cells have so much potential, why doesn't the body do more to exploit them when it is damaged by trauma or disease?

"We are looking at this question too. It may be that damage needs to be widespread before bone marrow stem cells are triggered to repair," said Prof Sharkis.

Another problem is how to interpret his experiment: does it show that the original cell in the bone marrow has unlimited potential? Or, when it migrates to another site in the body, are there local factors that reprogramme the migrating marrow cell to form a local stem cell?

"Both theories are possible, and this is a tough question that we are currently studying in my lab," says Prof Sharkis.

Dr Theise speculates that any healthy adult cell with an intact genetic code can be reprogrammed to become a stem cell. Evidence that this is the case has come from PPL Therapeutics, in Roslin, Scotland, the company that helped to clone Dolly the sheep.

Dr Alan Colman said that its American subsidiary has found a way to take adult skin cells, turn back the developmental clock to make stem cells without using cloning, then turn them into beating heart cells.

The past few days have also produced evidence that stem cells will fulfil their promise in medicine. One team, led by Dr Ronald McKay at the National Institutes of Health, Bethesda, has induced mouse embryonic stem cells to generate four cell types that self-assembled into what looked, and performed, like insulin-producing tissue clusters (islets) in the pancreas.

Dr McKay's study is the first to succeed in doing this, underlining how stem cells could be used to treat diabetes, a disease in which islet cells are destroyed.

The potential of using cells for brain repair has been demonstrated by other work, published in NeuroReport, in which lab-grown human neural stem cells were successfully transplanted for the first time into old rats and significantly improved their memory.

Aged rats that had received transplants of the human stem cells, parent cells of nerves, were able to perform memory tasks as well as younger rats without memory impairments, according to the study at the University of Illinois, Chicago, by Dr Kiminobu Sugaya and colleagues.

The transplantation of stem cells, followed by incorporation of the cells into the host brain, and subsequent cognitive improvement without rejection problems, is the first successful experiment of its kind.

"Previous studies have failed to produce working brain cells from transplants of stem cells," said Dr Sugaya.

"In our case, the stem cells were clearly incorporated into the host brain."

New insights into the dawn of human development have come from a unique combination of digital camera, microscope and computer at the new £12.5 million Institute of Reproductive and Developmental Biology at Imperial College, Hammersmith Hospital.

"Such pictures are helping to unravel why 80 per cent of human embryos are 'abnormal' with limited viability and how abnormal cells are regulated out of the system," says Lord Winston, the leading test-tube baby (IVF) researcher.

"They help understanding of genetic disease and these studies should also improve IVF treatments."

Sophie Spanos has used the computerised microscope to study human embryos in a warmed, protected environment. The embryos are left over after IVF treatment for infertility and studied only with permission of the parents.

The first image shows a two-celled embryo just after fertilisation. The next shows the six to eight-cell stage, on day three, when the cells are still totipotent, that is, each one can, in theory, form a separate human embryo. The third image shows the human embryo at day four. Now the cells are beginning to differentiate - turn into various basic cell types - and the definition between individual cells begins to blur, a process called compaction and morula formation.

The final frame shows the human embryo at day five. This hollow ball of cells is called a blastocyst, and is the last stage, before implantation into the womb, at which an embryo would be dismantled for stem cells for research.

The smudge at 10 o'clock is the inner cell mass, which will become the embryo proper after it has been implanted. Cells within it are pluripotent: they can give rise to any cell of the body.

-- Anonymous, May 14, 2001