Grow your own
Stem cell transplants tap into the body's own healing potential, writes David Tan
Imagine this: a car crash victim who suffers serious trauma to the brain avoids neurological damage after the doctors regenerate his lost brain matter using stem cells in the lab. In the future, this could become reality. A research team from Karolinska Institutet in Sweden has tried this in experimental trials on rats and mice with positive results.
At the scientific AAAS annual meeting in Boston yesterday, Paolo Macchiarini, a professor of regenerative surgery at Sweden's Karolinska Institute, revealed how pioneering stem cell-based transplant technology is being developed and tested on new organs and tissues. Macchiarini is renowned for a groundbreaking transplant in 2011 where a patient successfully received an artificial trachea (windpipe) covered in his own stem cells.
To date, five operations replacing diseased windpipes have been done using this technique. Next month, Macchiarini plans to operate on a two-year-old girl in the US who was born without a trachea and has lived her entire life in intensive care.
Macchiarini also plans to use the technique to recreate more complex tissues, such as the oesophagus and diaphragm, or organs such as the heart and lungs. "The aim is to make as much use of the body's own healing potential as we can," he says.
The term "stem cell" first appeared in scientific literature in 1868, when German biologist Ernst Haeckel used the phrase to describe the fertilised egg that becomes an organism, and also to describe the single-celled organism that acted as the ancestor cell to all living things in history. Scientists have been researching these cells for many years to unlock their secrets.
Most recently, the focus has been on induced pluripotent stem cells (iPSCs), which are generated by reprogramming a mature cell type into an immature state. These stem cells can then, in theory, be coaxed to become any type of specialised cell. They hold potential not only for drug development but also for studying disease.
A four-year-old boy born with a life-threatening irregular heartbeat was recently thrown a lifeline when researchers at Columbia University Medical Centre in New York devised a course of treatment based on the toddler's own iPSCs that were matured into heart muscle cells in the lab. Studies using these cells revealed that the child's condition, a congenital disorder called Long QT syndrome, was caused by the mutation of a particular gene.
Stem cells are unspecialised cells that generate copies of themselves as well as cells that mature into specialised cell types. There are two general types of stem cells: embryonic and adult. Embryonic stem cells are "master cells" and include stem cells made from embryos and iPSCs. They are pluripotent, which means they can develop into any tissue type in the body. Through a process called differentiation (maturation), a stem cell turns into a mature cell type such as a neuron or a muscle cell.
Adult stem cells are long-lived specialised stem cells that are able to maintain various tissues in the body throughout life. Some organs, such as the skin, are constantly turning over and rely on resident adult stem cells to maintain a constant supply of new cells.
Dr Alan Colman, executive director of the Singapore Stem Cell Consortium, believes that stem cell research is headed in two important directions. First, researchers are focusing on fine-tuning the maturation of pluripotent stem cells into cells of clinical relevance for drug discovery and testing. And second, iPSCs are being used to investigate the impact of genetic background on disease development.
"Every individual has a different genetic make-up, which influences drug reactions," says Colman. "We now have an opportunity through the development of iPSCs to study the underlying genetic and molecular causes of this without always having to test first on the patients or volunteers."
It was believed that specialised cells were restricted in their fate. But in 1962, British development biologist John Gurdon proved the opposite: that a specialised cell could return to its immature, pluripotent state. He replaced the immature cell nucleus in an egg cell of a frog with the nucleus from a mature intestinal cell. This modified egg cell developed into a normal tadpole.
More than 40 years later, in 2006, Professor Shinya Yamanaka of Kyoto University in Japan built on this finding, reprogramming mature cells to a pluripotent state by introducing just four genes.
Yamanaka's iPSC technology opens up exciting possibilities of using almost any cell type within the body to produce stem cells with unlimited potential. This paves the way for personalised medicine, where a patient's own cells could be used to derive pluripotent cells to repair damaged organs.
Both scientists were jointly awarded the 2012 Nobel Prize in physiology or medicine for their groundbreaking discoveries that have revolutionised our understanding of how cells and organisms develop.
Stem cell research has greatly enriched our understanding of how our bodies function. The gut lining renews itself every three to five days and is the most rapidly self-renewing tissue in the body. Gut stem cells generate all the different cell types in the intestine lining and scientists are working to understand how these stem cells function.
To do this, scientists use molecular markers on the cell surface and an example is a protein called Lgr5. Identified by a team led by Professor Nick Barker, now at the Institute of Medical Biology in Singapore, the protein is now widely used to study features of the gut stem cell.
Scientists use this knowledge to shed light on deadly diseases such as cancer. Barker and colleagues have discovered that the Lgr5-expressing stem cell is responsible for colon cancer, one of the biggest killers in the world and the second most common cancer in Hong Kong.
When a genetic mutation occurs in a stem cell that causes it to divide uncontrollably, a cancerous tumour forms. By virtue of a stem cell's ability to renew itself, many copies of actively proliferating cells are produced. This causes the tumour to grow.
Barker believes that with this knowledge, scientists are better able to design strategies to target cancer. "Now that we know that mutations in the stem cells are the cause of colon cancer, we can use this information to try to develop ways of selectively killing these dangerous cells in people who are most at risk of developing the disease during their lifetime."
Stem cell research is also opening up avenues for improving the detection of cancer. Dr Roberta Pang is a gastrointestinal stem cell specialist and assistant professor at the University of Hong Kong's department of surgery. At the Frontiers in Biomedical Sciences symposium held at HKU in December, Pang talked about how stem cell research is breaking new ground in the detection of metastasis in colon cancer.
Pang described a subset of cancer stem cells known as CD26-positive (CD26+) cells that not only initiate tumour growth in the colon but are capable of migrating to a distant organ, such as the liver, and propagating tumour growth there as well.
According to Pang, "CD26+ cancer stem cells can be readily detected in the peripheral blood of patients, and quantification of CD26+ in blood of colorectal cancer patients … can accurately serve as a prognostic marker to predict the development of metastasis."
While the application of iPSC technology in clinical therapy is still years in the making, some forms of stem cell therapy are already being used to treat deadly diseases.
Bone marrow transplantation has been developed over decades and is probably the best known form of stem cell therapy. It involves the use of blood stem cells to treat cancers such as leukaemia. After radiation that destroys both the patient's cancerous and healthy blood cells, blood stem cells from a donor are injected to replenish the patient's blood supply.
Stem cells derived from fat are being tested to treat a variety of diseases. Scientists believe that these cells, known as mesenchymal stem cells, have a regulatory effect on the immune system and may be used to treat multiple sclerosis. This is a disease where the immune system attacks components of nerves.
Stem cell therapies are not without risks. Transplanting donated stem cells, a process known as allogeneic transplantation, could cause compatibility problems. According to Lee Eng Hin, professor of orthopaedic surgery at the National University of Singapore, "Use of allogeneic mesenchymal stem cells carries risks such as immunogenicity and disease transmission as the cells are not from the same patient."
Another fear is that stem cells could grow in unexpected ways or could migrate elsewhere in the body and produce unwanted tissue. A Californian woman learned this the hard way when she had bits of bone growing in her face after fat stem cell injections, as was reported recently in Scientific American. To reduce the appearance of wrinkles, cosmetic surgeons had injected her face with dermal filler together with stem cells taken from her abdomen fat. Unfortunately, the principal component of the filler was a compound that stimulated her fat stem cells to transform into bone.
While this is an example of a stem cell treatment for cosmetic reasons, it nevertheless underlines the importance of understanding how stem cells might develop after being transplanted.
Another risk is the possibility of contamination when cells are extracted, treated and subsequently injected back into the body. In October last year, four women who underwent "skin revitalisation therapy" at a beauty salon at Causeway Bay were admitted to hospital with blood poisoning. One died from septic shock.
Pang sums up the situation: "Unfavourable incidents suggest that in stem cell treatments, there is always unanticipated interaction between stem cells and the microenvironment. Stem cell therapy technology is in its infancy and we are far from a state where scientists can completely control or regulate stem cell differentiation into specific cell types."
But research into stem cell transplants could lead scientists in new directions. For example, scientists hope to uncover signals and components made by stem cells, paving the way to design drugs that could stimulate the body to heal itself. Colman believes this to be an exciting time for stem cell research.
"Cell transfer experiments, as well as potentially providing benefit directly, may only be the prelude to the discovery, manufacture and clinical use of curative molecules made by stem cells, and future research will succeed in identifying these molecules and developing drugs based on their mode of action," Colman says.