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Creating and Growing Body Parts
by Gwen Lee

or millions of people, tissue engineering - the concept of growing living cells on templates to develop biological substitutes for damaged or diseased tissue - may be their only hope for a new lease of life.

After a slow start in the late 1980s, the multi- and interdisciplinary field of tissue engineering, which applies the principles of engineering to the life sciences, has caught on with scientists and clinicians around the world. This is fueled in part by donor-organ scarcity and problems like immunogenicity and infection associated with conventional tissue transplantation.

Currently, over 60 cell lines (six of which are from Singapore) have been developed from human embryonic stem cells worldwide. These non-specialized cells have the potential to be made to grow into any cell in the human body and offer hope in the fight against Alzheimer's disease, Parkinson's disease, diabetes, spinal-cord injury, and many other medical conditions.

The recent explosion of research has also revealed the enormous potential of human adult stem cells, commonly found in bone marrow. With the development of innovative biodegradable three-dimensional scaffold matrix and carrier materials on which stem cells can be seeded and grown in the laboratory, scientists can not only cultivate bone or cartilage cells but also come one step closer to growing such sophisticated and specific tissues as kidney, liver, and heart-muscle cells.

Unleashing the Potential of Embryonic Stem Cells

Singapore has been hailed as one of the world's leading producers of embryonic stem (ES) cell lines, thanks to the pioneering research of Professor Ariff Bongso and his associate Dr Fong Chui Yee at the Department of Obstetrics and Gynaecology, National University of Singapore (NUS). Indeed, in 1994 the scientists successfully isolated inner-cell-mass cells from human blastocysts and cultured them continuously in vitro for at least two generations. They published their findings, a world first that same year, in Human Reproduction.

The potential of human ES cells can best be described in the context of normal human development, which begins when a sperm fertilizes an egg to create a single cell from which all cell types can arise to form an entire complex organism.

Several cycles of cell division over five days result in a blastocyst - essentially a hollow ball of cells, lined inside with cells called the inner cell mass (ICM). Because ICM cells can differentiate into virtually every tissue of the human body, they are said to be pluripotent.

Bongso and his team, together with collaborative efforts from scientists at the Monash Institute of Reproduction, Australia, and the Hadassah Medical Center, Israel, have successfully developed six stem-cell lines compliant with the United States National Institutes of Health (NIH) guidelines. The researchers obtained the stem cells from six human embryos from the in vitro fertiltization (IVF) program at the National University Hospital (NUH), Singapore.

At present, no regulations governing such research exist here. Bongso stresses that since the local couples voluntarily donated the embryos and no payment changed hands, the stem-cell lines they generate are NIH-compliant. By the end of this year, the Bioethics Advisory Committee in Singapore, which was set up in December 2000, expects to issue ethical guidelines for research in this field. (Bioethics Advisory Committee website: www.bioethics-singapore.org/bac/index.jsp)

Bongso and his colleagues (Fong, Mark Richards, and Dr Chan Woon Khiong) remain the only group in Singapore whose work involves the use of ES cells, and they no longer need new human embryos to produce more cell lines. The initial six stem-cell lines have resulted in over 300 generations, and the team now has enough cells to supply various world organizations with research material.

Taking the groundbreaking research to the next level, NUS teamed up with the Monash Institute of Reproduction and Development, the Hadassah Medical Center of Israel, and the Hubrecht Laboratory of the Netherlands Institute of Developmental Biology to form a biotechnology company known as ES Cell International (ESCI) in July 2000. Jointly funded by the Economic Development Board of Singapore and a private investment group in Australia, the company now owns six stem-cell lines, most of which meet the NIH guidelines. Of the some 60 cell lines developed globally, about half may not be viable for research.

For now, ESCI focuses on identifying the factors that cause and control cell differentiation and on finding ways of directing the ES cells to make nerve and heart cells, and even islets of Langerhans - cells that produce insulin, the degeneration of which results in diabetes mellitus. Although ESCI's scientists have produced cells that look like and have even been confirmed as actual nerve and beating-heart cells, Bongso, the company's Singapore-based principal investigator, quickly points out that it will take another five to ten years before clinical applications can take place simply because too many questions of basic science remain unanswered.

Harnessing the Power of Adult Stem Cells

Although significant limitations exist, little doubt remains that adult stem cells found in differentiated tissues in children and adults hold real promise. Already a group from the Department of Orthopaedic Surgery, NUS, led by clinician Professor Lee Eng Hin (also Dean, Faculty of Medicine) and bioengineer Associate Professor James Goh, has succeeded in transplanting cartilage cultured from stem cells onto the growing bones of young children to correct angular deformities.

The clinicians first conducted the tissue-engineering therapy that put Singapore on the map when they worked in 1988 to rectify defects in the epiphyseal growth plates of children. This growth plate includes that layer of specialized bone and cartilage at the bone's end where new bone growth occurs as the child matures. If, as a result of trauma, part of the growth plate in, say, the leg bone sustains damage, one side of the bone will grow more than the other. The resulting discrepancy will cause the child to demonstrate an abnormal gait, and long-term problems may occur in the joints as a result of the uneven distribution of weight.

In their earlier work, the group had harvested chondrocytes (cartilage cells) directly from the pelvis to culture and insert into the damaged or defective growth plate. These cartilage cells were able to reorient themselves and soon became part of the growth plate, and bone growth reverted to normal. But the process of chondrocyte harvesting, which required a surgical procedure, proved to be a difficult experience for the patients. The team then started to grow mesenchymal stem cells (MSCs) which they could easily gather from the periosteum (the membrane of fibrous connective tissue surrounding the bone) via a simple biopsy.

(In classical medical teaching, students learn that as a blastocyst develops, the ICM will give rise to three layers: the ectoderm, the mesoderm, and the endoderm. The mesoderm is the layer that will differentiate into musculoskeletal tissues like bone, cartilage, connective tissue, muscle, and blood and skin. MSCs derive from the mesoderm; however, the origin of MSCs remains obscure, and more research needs to be carried out in this area.)

Lee's group achieved equally promising results when it transplanted the MSCs into the growth plate. For their outstanding research achievement, the NUS team received the Pediatric Orthopedic Society of North America Award in 1996. The group then went on to score a world first when it began clinical trials at NUH last year. So far, four children have had their bone deformities corrected by means of this procedure.

The group's work in using the primitive MSCs for articular (joint) cartilage repair has been successful too, and it has also demonstrated lasting and full-thickness restoration of such damaged cartilage. Consultants at NUH have successfully used this procedure in an ongoing clinical trial with more than 20 patients.

The Tissue Engineering Research Group in NUS/NUH places significant emphasis on the characterization of MSCs, having succeeded in isolating MSCs from the periosteum. In fact, Dr Suresh Nathan, a team member, recently won the Singapore Orthopaedic Association Annual Scientific Meeting's Young Investigator Award for his work on fat-derived MSCs (see story below). Another important component relies on the identification of the kind of growth factors required to stimulate MSCs to differentiate into specific cell types. Researchers know some of these growth factors; thus doctors can control some MSC differentiation, explains Goh.

As a global front-runner in this field, Goh and his team have also made headway in tendon-replacement research and have conceptualized ligament-transplant methods. Experiments have shown that they can regenerate tendon tissue in rabbit models in vivo by implanting a biodegradable scaffold matrix seeded with MSCs. Their next challenge is to create the right conditions for tendon tissue to grow in vitro. Because the scaffold takes more than four weeks to break down and be absorbed by the body to replace the ruptured tendon tissues, the joint has to be immobilized during the process. Hence, explains Goh, growing the tendon in the laboratory and then transplanting it into the joint can significantly shorten the patient's rehabilitation period. The same experimental model will apply once the ligament regeneration project takes off.

Another group of adult stem cells, known as hematopoietic stem cells (HSCs), has also come into the spotlight recently. Commonly found in bone marrow, HSCs can either replicate or give rise to blood cells. Along the way, some cells may digress and differentiate into highly sophisticated heart-muscle cells instead - a process known as transdifferentiation. Joining the worldwide race to mend broken hearts with bioengineered cardiac muscle is a Singapore team led by Associate Professor Reida El Oakley of the NUH Cardiac Department.

At present, heart disease remains the No. 2 killer in Singapore. The common causes of heart failure include heart attack, ischemia, and viral infection. Once damaged, the heart muscles become a mass of useless scar tissue, and the only way to regain total heart function is to substitute healthy tissue for the damaged portion.

In the laboratory, when researchers used live mice and transplanted HSCs into their ischemic hearts poorly supplied by blood, the organs actually gave rise to new heart-muscle cells and blood vessels. According to Oakley, such ischemic heart conditions as heart attacks produce ideal conditions to "persuade" HSC to specialize into cardiac-muscle cells and vascular tissue. His research has been submitted to an international medical journal for publication, and he hopes to begin clinical trials on heart-failure patients within a year.

Exciting breakthroughs are also happening in the arena of adult stem cells in the eye. Joining the ranks of the few laboratories doing pioneering work in this field is the Singapore Eye Research Institute. Team members are currently growing human ocular-surface stem cells and will soon be performing human corneal transplants. The institute is also trying to culture conjunctival stem cells for conjunctival transplantation in eyes affected by pterygium, a condition in which an opaque tissue film grows over the cornea.

The eye-research team is part of the Stem Cell Research Group located at the Outram Campus.

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