A complex disease


Chairperson of the Centre for Stem Cell Research and professor at the Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman.

The Star Online -Education

Published: Sunday June 28, 2015 MYT 12:00:00 AM 


Health tests: Hollywood actress Angelina Jolie said earlier this year that she has had her ovaries and Fallopian tubes removed over fears of cancer, following her double mastectomy two years ago. –  Reuters photo



The discovery of cancer stem cells and the use of therapeutic approaches may be a small but significant step towards tackling cancer.

A LONG-TIME friend Grace came into my office in tears one day. She was upset as her father and elder brother had died of cancer. And her younger brother had been diagnosed with colon cancer but chemotherapy was not working. She wondered if she would be diagnosed with cancer too. She asked why people were still dying of cancer every day despite all the cancer research.

Grace’s grief is not uncommon. We all know someone, including our immediate family, who has died of cancer.

There are at least two issues in Grace’s grief, namely a familiar trait of cancer risk, and why chemotherapy treatment often fails in cancer treatment. Though not identified, Grace’s family most likely carries one or more “faulty” genes, each of which has a 50% chance of passing on to the next generation.

Academy Award-winning actress Angelina Jolie was told that she carried a mutated, or “faulty” gene called BRCA1, an abbreviation for breast cancer gene. As a preventive step, she had both breasts, ovaries and fallopian tubes removed. Jolie may have increased her odds for a healthier life, but she is not free from cancer. No one is.

Cancer and cancer stem cells

Cancer is a complex disease. Besides hereditary genetic factors, cancer is horrendous in four other aspects, namely that: (i) cancer cells divide rapidly and uncontrollably; (ii) cancer cells can spread or metastasise to other body sites; metastasis is the major cause of cancer death; (iii) cancers can relapse or re-grow after surgical removal or other treatments; (iv) cancers often develop resistance to therapeutic drugs, therefore depriving cancer patients the use of a powerful armoury to combat the disease.

Is there a mastermind that is responsible for all such ghastly events in cancer? In recent years, a potential culprit called cancer stem cells have been discovered, which are thought to be responsible for metastasis, relapses and drug resistance.

Cancer stem cells (CSC) are present in a tumour mass in a very minute population. These cells are called cancer stem cells because they share the features of normal stem cells, which are the good guys, in being able to differentiate to give rise to other cell types. CSC may, therefore, generate multiple tumours through the self-renewal and differentiation properties of stem cells, leading to relapses and also giving the cancer cells mobility to spread to distant sites.

How does cancer develop resistance to chemotherapeutic drugs? Such an event is again linked to cancer stem cells. In the cell membrane of all normal cells, there are pumping stations, such as the ABC transporters, which are responsible for moving small molecules across the membrane. In cancer stem cells, such pumping stations are hyperactive in actively pumping out, and therefore removing therapeutic drugs from inside of the cancer cells. So while other surrounding cancer cells are being killed by the drug, cancer stem cells selectively survive the drug onslaught, and slowly become enriched in the tumour mass.

The discovery of cancer stem cells has shifted our thinking in battling cancer. Instead of just aiming to shrink the size of a tumour mass, it may now be imperative to think in terms of a search-and-destroy mission, targeting at cancer stem cells.

The CSC concept has provided new directions of designing novel therapeutic approaches to treat cancers. For example, all cells have a unique set of specific markers on the cell surface. Cancer stem cell-specific markers that distinguish them from other cancer or normal cells are being identified. Drugs may be developed to home in on such CSC-specific markers to selectively destroy CSC.

An example of such a drug, salinomycin, a veterinary drug, has indeed been identified by a team of Massachusetts Institute of Technology/ Harvard University scientists to be highly potent in killing CSCs. A common Indian spice, curcumin, also appears to be a CSC killer. As a further precaution, such drugs may be encapsulated in nanoparticles for controlled drug release in clinical protocols.

Stem cell-based therapy

The stem cell concept has also led to the development of stem cell-based cancer therapy. Prof Hans-Peter Kiem and his team at the Fred Hutchinson Cancer Research Centre, in Seattle, the United States, have developed “stem cell shield” to protect normal tissues, particularly the blood-generating bone marrow cells, from side effects of the anti-cancer drugs. Dr Khalid Shah of Massachusetts General Hospital and Harvard Medical School has genetically engineered stem cells into mini drug armouries to produce and secret toxin that specifically kills only brain tumours sparing normal cells.

In another angle of thinking, can we rein in cancer cells by reprogramming them into something else more controllable and less vicious? Prof Shinya Yamanaka from Kyoto University, Japan, was awarded the Nobel Prize in Physiology and Medicine in 2012 for developing a protocol for “reprogramming” cells to induce pluripotent stem cells, or iPSC. These reprogrammed cells have all the characteristics of stem cells in being able to convert into any cell types for regenerative purposes.

At the Faculty of Medicine and Health Sciences and the Centre of Stem Cell Research, Universiti Tunku Abdul Rahman (UTAR), we are the first in Malaysia to report on successful reprogramming of a number of cancer types into induced pluripotent cancer (iPC) cells, which are temporarily frozen in their expression of cancer features. Such iPCs are valuable in drug screening, in finding ways to reboot the damaged DNA repair mechanisms, and to be used as cancer study model in general.

Reprogramming can also be personalised because the reprogrammed cancer cells of a patient still carry the full set of delirious mutations. Such personalised reprogrammed cancer cells may then be used for rapid and accurate identification of the most effective drug for that particular cancer patient.

Cancer is so complex that it may never be totally conquered. The discovery of cancer stem cells and the use of stem cell-based cancer therapeutic approaches may only be a small but significant step towards the better tackling of cancer. Lots of work needs to be done, but we should remain hopeful that laboratory findings will one day be translated into clinical applications.

After that outburst in my office, I visited Grace when she calmed down. I told her that researchers may not have conquered cancer but they are still working hard to improve survival rates and the quality of life for cancer patients.

“Please do remember that the many vaccines we and our children use as preventive measures against diseases, the many drugs that allow us to control diabetes or blood pressure or cholesterol, the many diagnostic and therapeutic instruments and protocols that are being used daily worldwide to save lives are also the products of the efforts of hardworking researchers. Medical research is never a waste of taxpayers’ money. Medical research saves lives.”



Life renewed


Chairperson of the Centre for Stem Cell Research and professor at the Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman.

The Star Online -Education

Published: Sunday September 21, 2014 MYT 12:00:00 AM 



Advances in regenerative medicine point to a promising future for all humankind. JOHN Chen is 65 years old, and just retired. What worries Mrs Chen is that her husband is beginning to have difficulty in remembering where he has put his keys, or what he has read in a book after just a few hours.

After consulting a neurologist and doing a brain scan, John is diagnosed as showing the onset of Alzheimer's disease, a disease that is, at the time, already affecting one in a hundred people globally.

Fortunately, scientists have already pinpointed the parts of the brain that are affected. The neurologist decides to prescribe stem cell therapy for John. He scrubs a few cells from John’s tongue and asks John to return in two weeks for a precision injection of regenerated brain cells into the affected brain domains.

John’s life is back to normal after several injections, and enjoys his retirement with Mrs Chen for many years.

What is described may be a scene from 2030, or earlier. By that time, regenerative medicine would have been routinely used in treating human disorders involving impaired tissues or organs.

Not only can affected brain tissue be repaired for patients with Alzheimer's disease, defective hearts and kidneys can also be repaired or replaced through regenerated tissues.

The tools for making such dreams possible are stem cells, cells that already exist in our body, or cells, such as John’s tongue cells, that are coaxed into becoming stem cells through induction.

What are stem cells?

On fertilisation, an egg soon develops into a round entity of cells called the blastocyst, which soon implants itself on the uterine wall of the womb.

A small batch of cells, called the inner cell mass, or ICM, in the implanted blastocyst, immediately start to divide, or differentiate, into the three basic germ cell layers from which the limbs and all tissues and organs of our body are formed.

New life truly begins from the inner cell mass of an implanted blastocyst.

The ICM cells possess the potential to differentiate into all tissues and organs of our body. The more exciting news is that ICM cells may now be harvested and maintained in culture almost indefinitely in the laboratories.

Such cultured cells are called embryonicstem cells, or ESC. Like ICM, ESC bear the properties of being able to differentiate into different tissue types or organs such as the liver, kidney, pancreatic or neuron cells in the laboratory albeit by appropriation induction.

Embryonic stem cells are, therefore, pluripotent stem cells, with the plurality of differentiating potential.

In principle, ESC, when appropriately induced, can be clinically applied to repair impaired tissues, or one day to totally replace a damaged organ.

Unfortunately, an ESC line derived from a particular individual may not be clinically useful to other individuals due to rejection.

Besides such technical hindrances, ethical issues are also hampering further development of ESC for therapeutic treatments in the clinic.

Hence, other stem cell sources are needed for personalised applications of stem cell therapy.

Fortunately, many adult tissues also harbour mesenchymal stem cells, or MSC, which are also dubbed adult stem cells.

MSCs have now been routinely harvested from bone marrow, fat tissues, dental pulp and even in umbilical cord and cord blood, to name just a few major sources.

It is the discovery of stem cells in umbilical cord and cord blood that has driven the development of so-called stem cell banking by deep-freezing cord blood for future harvesting for personalised regenerative medicine applications, all eviating rejection and ethical issues.

Personalised therapy

MSC may be stem cells. Unlike ESC, however, MSCs of various sources are restricted in the tissue types from which they are derived.

In 2006, Prof Shinya Yamanaka and his team in Japan published a ground-breaking research paper describing the generation of induced pluripotent stem cells (iPSC) from mouse fibroblast cells by introducing four common and well-characterised factors into the cells.

iPSCs were shown to be ESC-like in being able to differentiate into the three germ layers of an embryo from which all tissues and organs are derived. In the following year, the first human iPSC lines were further reported by Prof Yamanaka.

Since then, laboratories around the world have been successful in generating, or reprogramming, thousands of iPSC lines from all kinds of adult tissues, even from cell lines derived from cancer or diseased organs and tissues. For this achievement, Prof Shinya Yamanaka was awarded the Nobel Prize in Medicine and Physiology in 2012, just six years after his first paper.

The other recipient of the 2012 Nobel Prize in Medicine and Physiology was Sir John Gurdon of the United Kingdom for his initial discovery that mature cells can be reprogrammed to become pluripotent cells.

But Sir John had to wait for many decades to receive the Nobel Prize until Professor Yamanaka’s work proved him right.

In short, we now have a laboratory protocol to generate pluripotent stem cells from exfoliated cells from the skin or tongue, or other tissue parts, of any patient, and coaxing them to regenerate desired tissues for tissue repair and engineering.

The current iPSC research directions are to improve on reprogramming efficiency, and to circumvent possible instability of iPS cells that might cause chromosomal mutations or to degenerate into cancerous cells on clinical applications.

An exciting new era

Hannah Warren was born without a trachea. In 2013, she had one trachea custom-made for her from plastic fibre with her own stem cells attached.

In another work published by an University of Edinburgh team in the August issue of the journal Nature Cell Biology, a whole thymus, a critical component of the immune system, was grown from transplanted and reprogrammed stem cells in mice.

This is a big step forward in regenerative medicine and tissue engineering in proving, in principle, that a whole functional organ could indeed be regenerated.

Limbal stem cells (LSC) are maintenance cells that serve to regularly repair and renew our cornea. Without LSC, the cornea would become cloudy, disrupting our vision. It has now been shown that LSC has the capacity to regenerate into new corneas.

If growing a windpipe, thymus and cornea was not challenging enough, what about growing a brain? In 2013, a paper published in Nature described the “growing” of “mini brains”, technically called "cerebral organoids", from adult stem cells.

If we could grow even a tiny fraction of our brain today, nothing can stop us from growing greater brain portions tomorrow.

Still dealing with the brain, researchers at the Imperial College, London, showed that infusing stem cells into the brain of stroke patients helped boost recovery by growing new blood vessels in the damaged brain areas. The treated patients were able to walk and to look after themselves six months after treatment.

It may sound like science fiction, but researchers are now developing ways of performing three-dimensional (3D) printing of body parts using stem cells. Such 3D-bioprinting would one day make it possible to “print” whole organs or crucial components of our body part as replacements.

These are only a few more newsworthy cases of recent successes in clinical applications of stem cell technologies.

Understandably, in such achievements as described above, the researchers always voice caution, stressing that realistic and safe clinical applications of stem cell therapeutic are still many years away.

The important thing is that the research community, working together with clinicians, have now truly embarked on that journey. This is reflected in the increasing political and industrial supports that stem cell research scientists are getting in the past and present years.

In Malaysia, apart from a small cluster of university academics with the foresight to know the importance of stem cell research, and who have been doing stem cell research with comparatively little financial support, we have not yet woken to the fast approaching storm of stem cell therapy.

Recognising the importance of stem cell research, Universiti Tunku Abdul Rahman (Utar) established the Centre for Stem Cell Research (CSCR) in June 2011, chaired by myself, and under the advice of Utar’s Faculty of Medicine and Health Sciences dean Emeritus Prof Dr Cheong Soon Keng.

In collaboration with Prof Dr Tunku Kamarul of Universiti Malaya’s Faculty of Medicine, and Dr Shigeki Sugii of Singapore Bio-imaging Consortium, Singapore, CSCR-Utar has now successfully generated iPSC lines from assorted cell types, including osteosarcoma and colon cancers cells as study models for human cancer.

We believe that the two iPSC research papers published recently in the tier-oneInternational Journal of Medical Sciences, by the Utar group, describe the first iPSC successes in Malaysia, and that CSCR-Utar is establishing itself as a hub in iPSC research in Malaysia.

To go further and to make regenerative medicine and tissue engineering a clinical possibility in Malaysia, solid financial support from the industry and the government, and true merging of the presently segmented academic and industry interest groups are crucial.

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