The stem cell map of the world

No branch of medicine is more complex or controversial – or has greater potential to transform our lives. Steve Connor assesses the global state of research

Stem cells have come to represent an almost magical transformation of medicine. It is hoped that they will be able to mend broken bones, fix damaged hearts, repair severed spinal cords, rejuvenate aged brains or generally treat any of the vital organs of an ailing patient. But what is the reality of these mysterious cells, which can transform themselves into any of the 200 specialised tissues of the human body?

Last month, the US Food and Drug Administration (FDA) gave the go-ahead for the first clinical trial of human embryonic stem cells on paralysed patients with spinal cord injuries. Geron, a Californian biotechnology company, has been licensed to use a line of stem cells isolated from human embryos left over from IVF treatment.

Stem cells are often described as the "master cells" of the body. But is probably more accurate to call them the "mothers" of all cells. A stem cell divides into two daughter cells and it is this process of cell division, from mother to daughter, that eventually turns a stem cell into one of the many specialist cells of the body – whether it is an insulin-producing cell in the pancreas, or a nerve cell in the brain.

The vital point about a stem cell is that it has a potency that other cells do not possess. But not all stem cells have the same power. The greatest of all stem cells is the zygote, or fertilised egg. This single cell has the power of creating every single cell of the body.

The next level of potency is possessed by stem cells derived from early embryos – a few days after fertilisation. These embryonic stem cells are able to form all of the body's cell lineages, including the germ cells that give rise to sperm and eggs. However, these cells on their own, and without any intervention, do not normally give rise to a complete person, which is why their potency is somewhat more limited.

Further down the hierarchy of power comes "multipotency". This is when a stem cell can form multiple lineages of cells that constitute an entire tissue or set of related tissues. A good example of this type of potency is the stem cells that come from a person's bone marrow. These stem cells give rise to some of the many different cells of the blood and the immune system. Another example is the stem cells found in the blood of the umbilical cord and placenta. Like bone marrow stem cells, cord blood stem cells can also differentiate into different specialised cells of the blood and immune system.

The embryonic stem cell,which develops a few days after the fertilised egg begins to divide, is the stem cell that holds the most promise as the ultimate "repair kit" for the human body. The aim, eventually, is to be able to make embryonic stem cells from a patient's own skin in order to transplant them back into the body and fix whatever has been damaged. Scientists all over the world are engaged in the race to develop stem cell therapies.



Around the world: The stem cell map



A first for primate cloning: Beaverton, Oregon

Shoukhrat Mitalipov, a Russian-born scientist working at the Oregon National Primate Research Centre, used the Dolly technique to clone primate embryos from the skin cells of a 10-year-old rhesus macaque monkey called Semos. They were the first primate embryos to be cloned in this way. He also extracted embryonic stem cells from some of the cloned embryos and managed to get some of these embryonic cells to develop in the laboratory into mature heart cells and brain neurons, according to a study published at the end of 2007.





Dolly the sheep: Roslin, Edinburgh, Scotland:

A team led by Ian Wilmut of the Roslin Institute near Edinburgh announced in 1996 the birth of Dolly the sheep, who was cloned from the frozen udder cells of a six-year-old ewe. Dolly was the first authenticated clone of an adult mammal and her birth marked a milestone in the possible derivation of embryonic stem cells from adult mammals, such as man. The implications for medicine are immense – in that it raised the possibility of making a "repair kit" of embryonic stem cells from a patient's own skin cells in order to mend damaged tissues in the brain, heart, pancreas or virtually any other part of an ailing body.

Man meets cow: Newcastle, England

Alison Murdoch of Newcastle University's Centre for Life announced, in May 2005, the creation of human blastocyst embryos produced by a modified version of the Dolly cloning technique, where the nuclei of embryonic stem cells are inserted into human eggs with their own nuclei removed. However, Murdoch's colleague, Miodrag Stojkovic, subsequently severed ties with her, claiming that the work was announced prematurely and without due credit. He left Newcastle to lead the Prince Felipe Research Centre in Valencia, Spain in 2006. Since then, Newcastle's stem cell work has been led by Lyle Armstrong, who has produced 278 cloned "hybrid" embryos created by the fusion of human cells with cow eggs. However, he has been unable to extract embryonic stem cells from hybrid embryos and has run out of funding.

Human embryos and controversy: Seoul, South Korea

Cloning expert Woo Suk Hwang of Seoul National University in South Korea announced in February 2004 the world's first successful clones of human embryos in a study published in the journal 'Science'. Wang used the Dolly technique to transfer cell nuclei from skin cells into human eggs that had their own DNA removed. In May 2005, they announced a streamlined process that used far fewer human eggs and in November 2005 they announced the establishment of 11 "lines" of embryonic stem cell from cloned human embryos. However, over the next few months the studies were retracted, Wang admitted scientific fraud and was forced to resign in disgrace.

Skin genes reprogrammed: Kyoto, Japan

Shinya Yamanaka of Kyoto University is the first to change the face of embryonic stem cell research using a pioneering approach called "direct reprogramming", which involves altering a handful of genes in an adult skin cell so that it reverts to an embryonic-like state without the need for eggs or embryos. In 1996, Yamanaka showed that the approach, called induced pluripotent stem (IPS) cells, works on mice cells and in 2007 he demonstrated that it could also be done successfully on human cells. A separate study by James Thomson's group in Wisconsin came to the same conclusion.

The mouse stem cells breakthrough: San Francisco, California

Two groups working independently, led by Gail Martin of the University of California, San Francisco, and Martin Evans of the University of Cambridge, isolated embryonic stem cells for the first time from laboratory mice in pioneering studies published in 1981. Professor Evans went on to lay the foundation for much of the later work on human embryonic stem cells. Crucially, he showed that mouse embryonic stem cells could give rise to all cells of the body, including the germ cells that produce sperm and eggs, a breakthrough that won him a share of the 2007 Nobel prize for medicine.

Advance for spinal injuries? Madison, Wisconsin and Menlo Park, California

James Thomson of the Wisconsin Regional Primate Research Centre is the first to extract embryonic stem cells from primates – rhesus macaque monkeys – in a study published in 1995. In November 1998, he was the first to isolate human embryonic stem cells from human embryos left over from IVF treatment. Patents for the Wisconsin stem cells are granted the Wisconsin Alumni Research Foundation and the technology is commercialised by biotechnology company Geron of Menlo Park, California. In January 2009, Geron is granted a licence by the FDA to begin clinical trials on spinal cord patients.

A false start: Worcester, Massachusetts

The Massachusetts laboratory facility of the company Advanced Cell Technology announced in 2001 that it had cloned a human embryo with the aim of producing bespoke human embryonic stem cells for patients. However, the evidence proved controversial and was not conclusive. The three-day-old embryo did not develop past the stage of a few cells. The company was also the first to experiment with "hybrid" embryos, by fusing human cells with cow eggs. In 2006, the company announced another technique for deriving embryonic stem cells from an embryo that does not destroythat embryo.

The landmark trachea transplant: Barcelona, Spain

In 2008, a 30-year-old woman became the first patient to receive a bio-engineered windpipe – the trachea – grown from her own stem cells. Tuberculosis destroyed the windpipe of Claudia Castillo, so scientists from Barcelona's Hospital Clinic, working with colleagues from Bristol University, took stem cells from her bone marrow and from within the inside of her nose to make cartilage and epithelial tissue to reconstruct the organ, which they successfully transplanted into the patient. Castillo can now walk up stairs and play with her children – activities that were impossible for her before the pioneering operation.

Rabbit fusion: Shanghai, China

In 2003, a team of scientists led by Hui Zhen Sheng of the Shanghai Second Medical University published a study showing that it is possible to fuse human cells with the enucleated egg cells of animals – in this case the rabbit – to produce embryonic stem cells. Sheng effectively used a version of the Dolly cloning technique of cell nuclear transfer and bypassed the problem of a shortage of human eggs by using rabbit eggs that had their own nuclei removed. She was able to report the isolation of embryonic stem cells from these hybrid cloned embryos derived from the skin cells of four people aged five, 42, 52 and 60. She also reported being able to grow these stem cells into muscle and nerve cells. However, other scientists have yet to replicate the work.

Asia's stem cell bank: Singapore

The city state has attracted many stem cell researchers from around the world with its liberal laws on embryonic stem cells and human embryo cloning, as well as generous research funding. American scientists, dogged by restrictions on US federal funding of embryonic stem cell research and British scientists, complaining of poor funding in the UK, have been enticed to work in the city, which has built up a sizeable stem cell bank at Biopolis, a seven-building biomedical "hive" of activity, and gleaming centrepiece of Singapore's biotechnology industry.

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